Compounds modulating c-fms and/or c-kit activity and uses therefor

ABSTRACT

Compounds active on the receptor protein tyrosine kinases c-kit and/or c-fms are provided herewith. Also provided herewith are compositions useful for treatment of c-kit mediated diseases or conditions and/or c-fms-mediated diseases or conditions, and methods for the use thereof.

RELATED PATENT APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/546,923, filed Jul. 11, 2012, which is a continuation of U.S. patentapplication Ser. No. 12/958,379, filed Dec. 1, 2010, which is adivisional application of U.S. patent application Ser. No. 11/986,667,filed Nov. 21, 2007, now U.S. Pat. No. 7,893,075, issued Feb. 22, 2011,which claims priority to U.S. Provisional App. No. 60/860,749, filedNov. 22, 2006, and is related to U.S. patent application Ser. No.11/435,381, filed May 16, 2006, now U.S. Pat. No. 7,846,941, whichclaims the benefit of U.S. Provisional App. No. 60/682,063, filed May17, 2005, U.S. Provisional App. No. 60/682,051, filed May 17, 2005, U.S.Provisional App. No. 60/682,042, filed May 17, 2005, U.S. ProvisionalApp. No. 60/692,750, filed Jun. 22, 2005, and U.S. Provisional App. No.60/692,960, filed Jun. 22, 2005, all of which are incorporated herein byreference in their entireties and for all purposes.

FIELD OF THE INVENTION

This invention relates to ligands for c-fms and c-kit, and to methodsfor use thereof. The information provided is intended solely to assistthe understanding of the reader. None of the information provided norreferences cited is admitted to be prior art to the present invention.Each of the references cited is incorporated herein in its entirety andfor any purpose.

BACKGROUND OF THE INVENTION

C-fms and c-kit are both type III transmembrane receptor proteintyrosine kinases (RPTKs) that regulate key signal transduction cascadesthat control cellular growth and proliferation. Both receptors havesimilar structural features comprising five extracellular immunoglobulin(IG) domains, a single transmembrane domain, and a split cytoplasmickinase domain separated by a kinase insert segment.

c-Fms

C-fms is a member of the family of genes originally isolated from theSusan McDonough strain of feline sarcoma viruses. The cellularproto-oncogene FMS (c-fms, cellular feline McDonough sarcoma) codes forthe receptor for the macrophage colony-stimulating factor (M-CSF). C-fmsis crucial for the growth and differentiation of the monocyte-macrophagelineage, and upon binding of M-CSF to the extracellular domain of c-fms,the receptor dimerizes and trans-autophosphorylates cytoplasmic tyrosineresidues.

M-CSF, first described by Robinson and co-workers (Blood. 1969,33:396-9), is a cytokine that controls the production, differentiation,and function of macrophages. M-CSF stimulates differentiation ofprogenitor cells to mature monocytes, and prolongs the survival ofmonocytes. Furthermore, M-CSF enhances cytotoxicity, superoxideproduction, phagocytosis, chemotaxis, and secondary cytokine productionof additional factors in monocytes and macrophages. Examples of suchadditional factors include granulocyte colony stimulating factor(G-CSF), interleukin-6 (IL-6), and interleukin-8 (IL-8). M-CSFstimulates hematopoiesis, promotes differentiation and proliferation ofosteoclast progenitor cells, and has profound effects on lipidmetabolism. Furthermore, M-CSF is important in pregnancy.Physiologically, large amounts of M-CSF are produced in the placenta,and M-CSF is believed to play an essential role in trophoblastdifferentiation (Motoyoshi, Int J. Hematol. 1998, 67:109-22). Theelevated serum levels of M-CSF in early pregnancy may participate in theimmunologic mechanisms responsible for the maintenance of the pregnancy(Flanagan & Lader, Curr Opin Hematol. 1998, 5:181-5).

Related to c-fms and c-kit are two platelet-derived growth factorreceptors, alpha (i.e., pdgfra) and beta (pdgfrb) (PDGF). The genecoding for pdgfra is located on chromosome 4q11-q12 in the same regionof chromosome 4 as the oncogene coding for c-kit. The genes coding forpdgfra and c-fms appear to have evolved from a common ancestral gene bygene duplication, inasmuch as these two genes are tandemly linked onchromosome 5. They are oriented head-to-tail with the 5-prime exon ofthe c-fms gene located only 500 bp from the last 3-prime exon of thegene coding for pdgfra. Most gastrointestinal stromal tumors (GIST) haveactivating mutations in c-kit, and most patients with GISTs respond wellto Gleevec, which inhibits c-kit. Heinrich et al. (Science 2003,299:708-10) have shown that approximately 35% of GISTs lacking c-kitmutations have intragenic activation mutations in the gene encodingpdgfra, and that tumors expressing c-kit or pdgfra are indistinguishablewith respect to activation of downstream signaling intermediates andcytogenetic changes associated with tumor progression. Thus, c-kit andpdgfra mutations appear to be alternative and mutually exclusiveoncogenic mechanisms in GISTs.

Similarly, the observation that production of M-CSF, the majormacrophage growth factor, is increased in tissues during inflammationpoints out a role for c-fms in diseases, such as for exampleinflammatory diseases. More particularly, because elevated levels ofM-CSF are found in the disease state, modulation of the activity ofc-fms can ameliorate disease associated with increased levels of M-CSF.

c-Kit

The Stem Cell Factor (SCF) receptor c-kit plays an important role in thedevelopment of melanocytes and mast, germ and hematopoietic cells. StemCell Factor (SCF) is a protein encoded by the 51 locus, and has alsobeen called “kit ligand” (KL) and mast cell growth factor (MGF), basedon the biological properties used to identify it (reviewed in Tsujimura,Pathol Int 1996, 46:933-938; Loveland, et al., J. Endocrinol 1997,153:337-344; Vliagoftis, et al., Clin Immunol 1997, 100:435-440; Broudy,Blood 1997, 90:1345-1364; Pignon, Hermatol Cell Ther 1997, 39:114-116;and Lyman, et al., Blood 1998, 91:1101-1134.). Herein the abbreviationSCF refers to the physiological ligand for c-kit.

SCF is synthesized as a transmembrane protein with a molecular weight of220 or 248 Dalton, depending on alternative splicing of the mRNA toencode exon 6. The larger protein can be proteolytically cleaved to forma soluble, glycosylated protein which noncovalently dimerizes. Both thesoluble and membrane-bound forms of SCF can bind to and activate c-kit.For example, in the skin, SCF is predominantly expressed by fibroblasts,keratinocytes, and endothelial cells, which modulate the activity ofmelanocytes and mast cells expressing c-kit. In bone, marrow stromalcells express SCF and regulate hematopoiesis of c-kit expressing stemcells. In the gastrointestinal tract, intestinal epithelial cellsexpress SCF and affect the interstitial cells of Cajal andintraepithelial lymphocytes. In the testis, sertoli cells and granulosacells express SCF which regulates spermatogenesis by interaction withc-kit on germ cells.

SUMMARY OF THE INVENTION

The present invention relates to compounds active on c-fms, c-kit, orboth c-fms and c-kit. In accordance with one aspect of the presentinvention, it has been discovered that in the treatment of diseasesamenable to treatment by an effective amount of a modulator of eitherc-fms alone or c-kit alone, the efficacy of treatment can be enhanced ifsaid compounds are dual inhibitors of both c-fms and c-kit. In anotheraspect of the present invention, compounds active on c-fms, c-kit, orboth c-fms and c-kit are also active on one or more of TrkA, TrkB andHGK. In particular, the invention provides compounds of Formula I, andall sub-generic formulae thereof, as well as methods of using suchcompounds as described below. Thus, the invention provides methods ofusing compounds that can be used therapeutically and/or prophylacticallyinvolving modulation of c-fms, c-kit, or both c-fms and c-kit, orinvolving one or more of TrkA, TrkB and HGK in addition to c-fms, c-kit,or both c-fms and c-kit.

The compounds of Formula I have the following structure:

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   X₁ is N or CR², X₂ is N or CR⁶, Y₁ is N or CR⁴, and Y₂ is N or        CR⁵, provided, however, that not more than one of X₂, Y₁ and Y₂        is N;    -   L¹ is selected from the group consisting of optionally        substituted lower alkylene, —S—, —O—, —C(O)—, —C(S)—, —S—(O)—,        —S(O)₂—, and —NR⁷—;    -   L² is selected from the group consisting of a bond, optionally        substituted lower alkylene, -(alk)_(a)-S-(alk)_(b)-,        -(alk)_(a)-O-(alk)_(b)-, -(alk)_(a)-OC(O)-(alk)_(b)-,        -(alk)_(a)-C(O)O-(alk)_(b)-, -(alk)_(a)-OC(S)-(alk)_(b)-,        -(alk)_(a)-C(S)O-(alk)_(b)-, -(alk)_(a)-C(O)-(alk)_(b)-,        -(alk)_(a)-C(S)-(alk)_(b)-, -(alk)_(a)-C(O)NR⁹—(alk)_(b)-,        -(alk)_(a)-OC(O)NR⁹—(alk)_(b)-, -(alk)_(a)-OC(S)NR⁹—(alk)_(b)-,        -(alk)_(a)-C(S)NR⁹—(alk)_(b)-, -(alk)_(a)-S(O)-(alk)_(b)-,        -(alk)_(a)-S(O)₂-(alk)_(b)-, -(alk)_(a)-S(O)₂NR⁹—(alk)_(b)-,        -(alk)_(a)-NR⁹—(alk)_(b)-, -(alk)_(a)-NR⁹C(O)-(alk)_(b)-,        -(alk)_(a)-NR⁹C(S)-(alk)_(b)-, -(alk)_(a)-NR⁹C(O)NR⁹—(alk)_(b)-,        -(alk)_(a)-NR⁹C(S)NR⁹—(alk)_(b)-,        -(alk)_(a)-NR⁹C(O)O-(alk)_(b)-, -(alk)_(a)-NR⁹C(S)O-(alk)_(b)-,        -(alk)_(a)-NR⁹S(O)₂-(alk)_(b)-, and        -(alk)_(a)-NR⁹S(O)₂NR⁹—(alk)_(b)-, wherein alk is optionally        substituted C₁₋₃ alkylene and a and b are independently 0 or 1;    -   R¹ is selected from the group consisting of optionally        substituted lower alkyl, optionally substituted cycloalkyl,        optionally substituted heterocycloalkyl, optionally substituted        aryl, and optionally substituted heteroaryl;    -   R², R⁴, R⁵ and R⁶ are independently selected from the group        consisting of hydrogen, halogen, optionally substituted lower        alkyl, optionally substituted lower alkenyl, optionally        substituted lower alkynyl, optionally substituted cycloalkyl,        optionally substituted heterocycloalkyl, optionally substituted        aryl, optionally substituted heteroaryl, —OH, —NH₂, —NO₂, —CN,        —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂,        —NHC(S)NH₂, —NHS(O)₂NH₂, —NR¹⁰R¹¹, —NHR³, —OR³, —SR³, —C(O)R³,        —C(S)R³, —S(O)R³, —S(O)₂R³, —C(O)OR³, —C(S)OR³, —C(O)NHR³,        —C(O)NR³R³, —C(S)NHR³, —C(S)NR³R³, —S(O)₂NHR³, —S(O)₂NR³R³,        —NHC(O)R³, —NR³C(O)R³, —NHC(S)R³, —NR³C(S)R³, —NHS(O)₂R³,        —NR³S(O)₂R³, —NHC(O)OR³, —NR³C(O)OH, —NR³C(O)OR³, —NHC(S)OR³,        —NR³C(S)OH, —NR³C(S)OR³, —NHC(O)NHR³, —NHC(O)NR³R³, —NR³C(O)NH₂,        —NR³C(O)NHR³, —NR³C(O)NR³R³, —NHC(S)NHR³, —NHC(S)NR³R³,        —NR³C(S)NH₂, —NR³C(S)NHR³, —NR³C(S)NR³R³, —NHS(O)₂NHR³,        —NHS(O)₂NR³R³, —NR³S(O)₂NH₂, —NR³S(O)₂NHR³, and —NR³S(O)₂NR³R³;    -   Ar₁ is a 5 or 6 membered optionally substituted heteroarylene        having the structure

-   -   wherein

indicates the point of attachment of L¹ and

indicates the point of attachment of L², and wherein the indicated N iseither ═N— or —N═;

-   -   n is 0 or 1;    -   F and J are both C or one of F and J is C and the other of F and        J is N;    -   P and Q are independently selected from CR, N, NR, O or S;    -   T is selected from CR or N;        -   wherein            -   when n is 1, F and J are C, and P, T and Q are CR, or                any one of P, T and Q is N and the other two of P, T and                Q are CR,            -   when n is 0 and F and J are both C, then one of P and Q                are CR, N or NR and the other of P and Q is C, N, NR, O                or S, provided both P and Q are not CR,            -   when n is 0, one of F and J is N and the other of F and                J is C, then one of P and Q is N and the other of P and                Q is CR or both P and Q are CR, and            -   R is hydrogen or an optional substituent as defined                herein for optionally substituted heteroarylene that                provides a stable compound;    -   R³ at each occurrence is independently selected from the group        consisting of optionally substituted lower alkyl, optionally        substituted lower alkenyl, provided, however, that no alkene        carbon thereof is bound to any —C(O)—, —C(S)—, —S(O)—, —S(O)₂—,        —O—, —S—, or —N— of any of —OR³, —SR³, —C(O)R³, —C(S)R³,        —S(O)R³, —S(O)₂R³, —C(O)OR³, —C(S)OR³, —C(O)NHR³, —C(O)NR³R³,        —C(S)NHR³, —C(S)NR³R³, —S(O)₂NHR³, —S(O)₂NR³R³, —NHR³,        —NHC(O)R³, —NR³C(O)R³, —NHC(S)R³, —NR³C(S)R³, —NHS(O)₂R³,        —NR³S(O)₂R³, —NHC(O)OR³, —NR³C(O)OH, —NR³C(O)OR³, —NHC(S)OR³,        NR³C(S)OH, —NR³C(S)OR³, —NHC(O)NHR³, —NHC(O)NR³R³, —NR³C(O)NH₂,        —NR³C(O)NHR³, —NR³C(O)NR³R³, —NHC(S)NHR³, —NHC(S)NR³R³,        —NR³C(S)NH₂, —NR³C(S)NHR³, —NR³C(S)NR³R³, —NHS(O)₂NHR³,        —NHS(O)₂NR³R³, —NR³S(O)₂NH₂, —NR³S(O)₂NHR³, or —NR³S(O)₂NR³R³,        optionally substituted lower alkynyl, provided, however, that no        alkyne carbon thereof is bound to any —C(O)—, —C(S)—, —S(O)—,        —S(O)₂—, —O—, —S—, or —N— of any of —OR³, —SR³, —C(O)R³,        —C(S)R³, —S(O)R³, —S(O)₂R³, —C(O)OR³, —C(S)OR³, —C(O)NHR³,        —C(O)NR³R³, —C(S)NHR³, —C(S)NR³R³, —S(O)₂NHR³, —S(O)₂NR³R³,        —NHR³, —NHC(O)R³, —NR³C(O)R³, —NHC(S)R³, —NR³C(S)R³, —NHS(O)₂R³,        —NR³S(O)₂R³, —NHC(O)OR³, —NR³C(O)OH, —NR³C(O)OR³, —NHC(S)OR³,        —NR³C(S)OH, —NR³C(S)OR³, —NHC(O)NHR³, —NHC(O)NR³R³, —NR³C(O)NH₂,        —NR³C(O)NHR³, —NR³C(O)NR³R³, —NHC(S)NHR³, —NHC(S)NR³R³,        —NR³C(S)NH₂, —NR³C(S)NHR³, —NR³C(S)NR³R³, —NHS(O)₂NHR³,        —NHS(O)₂NR³R³, —NR³S(O)₂NH₂, —NR³S(O)₂NHR³, or —NR³S(O)₂NR³R³,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl, and optionally        substituted heteroaryl;    -   R⁷ is selected from the group consisting of hydrogen, optionally        substituted lower alkyl, optionally substituted cycloalkyl,        optionally substituted heterocycloalkyl, optionally substituted        aryl, optionally substituted heteroaryl, —C(O)R⁸, and —S(O)₂R⁸;    -   R⁸ is selected from the group consisting of optionally        substituted lower alkyl, optionally substituted cycloalkyl,        optionally substituted heterocycloalkyl, optionally substituted        aryl and optionally substituted heteroaryl;    -   R⁹ at each occurrence is independently selected from the group        consisting of hydrogen, lower alkyl, and lower alkyl substituted        with one or more substituents selected from the group consisting        of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, fluoro substituted mono-alkylamino,        di-alkylamino, fluoro substituted di-alkylamino, and —NR¹²R¹³,        provided, however, that when R⁹ is substituted lower alkyl, any        substitution on the alkyl carbon bound to the —N— of —NR⁹— is        fluoro;    -   R¹⁰ and R¹¹ at each occurrence are independently selected from        the group consisting of optionally substituted lower alkyl,        optionally substituted lower alkenyl, provided, however, that no        alkene carbon thereof is bound to the nitrogen of —NR¹⁰R¹¹,        optionally substituted lower alkynyl, provided, however, that no        alkyne carbon thereof is bound to the nitrogen of —NR¹⁰R¹¹,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl, and optionally        substituted heteroaryl; or    -   R¹⁰ and R¹¹ together with the nitrogen to which they are        attached form a monocyclic 5-7 membered optionally substituted        heterocycloalkyl or a monocyclic 5 or 7 membered optionally        substituted nitrogen containing heteroaryl; and    -   R¹² and R¹³ combine with the nitrogen to which they are attached        to form a 5-7 membered heterocycloalkyl or 5-7 membered        heterocycloalkyl substituted with one or more substituents        selected from the group consisting of fluoro, —OH, —NH₂, lower        alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro        substituted lower alkoxy, lower alkylthio, and fluoro        substituted lower alkylthio;    -   provided, however that when compounds have the structure

-   -   and L^(1a) is —CH₂—, —CH(OH)—, or —C(O)—, then R^(1a) is not        phenyl, 4-trifluoromethyl-phenyl, 4-methoxy-phenyl,        4-chloro-phenyl, 4-fluoro-phenyl, 4-methyl-phenyl,        3-fluoro-phenyl or thiophen-2-yl, and compounds do not have the        structure

In reference to Formula I, the core structure shown above with X₁, X₂,Y₁ and Y₂ as CH and with L¹-Ar₁-L²-R¹ replaced with H is referred to asthe “azaindole core.” For that azaindole core, reference to ring atomsor ring positions is as shown in the following structure:

In one embodiment of compounds of Formula I, compounds have a structureselected from the following:

wherein L¹, Ar₁, L², R¹, R², R⁴, R⁵ and R⁶ are as defined for Formula I.

In one embodiment of compounds of Formula I, X₁ and X₂ are N or CH. Inanother embodiment, X₁, X₂ and Y₁ are N or CH, where in a furtherembodiment, Y₂ is CR⁵ and R⁵ is other than hydrogen. In anotherembodiment, X₁, X₂ and Y₂ are N or CH, where in a further embodiment Y₁is CR⁴ and R⁴ is other than hydrogen. In another embodiment, X₁, X₂ andY₁ are CH, where in a further embodiment, Y₂ is CR⁵ and R⁵ is other thanhydrogen. In another embodiment, X₁, X₂ and Y₂ are CH, where in afurther embodiment Y₁ is CR⁴ and R⁴ is other than hydrogen.

In one embodiment of compounds of Formula I, wherein X₁, X₂, Y₁ and Y₂are independently CR², CR⁶, CR⁴ and CR⁵ respectively, one of R⁴ or R⁵ isother than hydrogen, preferably where R² and R⁶ are hydrogen. In oneembodiment, wherein X₁, X₂, Y₁ and Y₂ are independently CR², CR⁶, CR⁴and CR⁵ respectively, R², R⁵ and R⁶ are hydrogen and R⁴ is other thanhydrogen. In one embodiment, wherein X₁, X₂, Y₁ and Y₂ are independentlyCR², CR⁶, CR⁴ and CR⁵ respectively, R², R⁴ and R⁶ are hydrogen and R⁵ isother than hydrogen.

In one embodiment of compounds of Formula I, X₁ and X₂ are N or CH,preferably wherein both X₁ and X₂ are CH.

In one embodiment of compounds of Formula I, L¹ is selected from thegroup consisting of —S—, —O—, lower alkylene, —C(O)—, —C(S)—, —S(O)—,—S(O)₂—, and —NR⁷—, wherein lower alkylene is optionally substitutedwith fluoro, and wherein when L² is optionally substituted loweralkylene or comprises optionally substituted C₁₋₃ alkylene, the alkyleneis optionally substituted with fluoro or lower alkyl. In one embodiment,L¹ is selected from the group consisting of —S—, —O—, —CH₂—, —CF₂—,—C(O)—, —C(S)—, —S(O)—, —S(O)₂—, and —NH—.

In one embodiment of compounds of Formula I, L² is selected from thegroup consisting of a bond, optionally substituted lower alkylene,—O-(alk)_(b)-, —OC(O)-(alk)_(b)-, —C(O)O-(alk)_(b)-, —OC(S)-(alk)_(b)-,—C(S)O-(alk)_(b)-, —C(O)-(alk)_(b)-, —C(S)-(alk)_(b)-,—C(O)NR⁹—(alk)_(b)-, —OC(O)NR⁹—(alk)_(b)-, —OC(S)NR⁹—(alk)_(b)-,—C(S)NR⁹—(alk)_(b)-, —S(O)-(alk)_(b)-, —S(O)₂-(alk)_(b)-,S(O)₂NR⁹—(alk)_(b)-, —NR⁹—(alk)_(b)-, —NR⁹C(O)-(alk)_(b)-,—NR⁹C(O)O-(alk)_(b)-, —NR⁹C(S)-(alk)_(b)-, —NR⁹C(S)O-(alk)_(b)-,—NR⁹C(O)NR⁹—(alk)_(b)-, —NR⁹C(S)NR⁹—(alk)_(b)-, —NR⁹S(O)₂-(alk)_(b)-,and —NR⁹S(O)₂NR⁹—(alk)_(b)-.

Further to any of the above embodiments of Formula I, when L¹ issubstituted lower alkylene or when L² is substituted lower alkylene orcomprises substituted C₁₋₃ alkylene, the alkylene is substituted withone or more, preferably 1, 2, or 3 substituents selected from the groupconsisting of fluoro, —OH, —NH₂, lower alkoxy, lower alkylthio,mono-alkylamino, di-alkylamino, and —NR¹²R¹³, wherein the alkyl chain(s)of lower alkoxy, lower alkylthio, mono-alkylamino or di-alkylamino areoptionally substituted with one or more, preferably 1, 2, or 3substituents selected from the group consisting of fluoro, —OH, —NH₂,lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluorosubstituted lower alkylthio, mono-alkylamino, di-alkylamino, orcycloalkylamino.

In one embodiment of the compounds of Formula I, the variables P, J, Q,T, F, and n are selected to provide structures of Ar₁ selected from thegroup consisting of

where each R is independently hydrogen or an optional substituent asdefined herein for optionally substituted heteroaryl.

In one embodiment, a compound of Formula I has a structure according tothe following sub-generic structure, Formula Ia,

all salts, prodrugs, tautomers, and isomers thereof,wherein L¹, Ar₁, R¹, R², R⁴, R⁵ and R⁶ are as defined for Formula I;

-   -   L³ is selected from the group consisting of a bond, optionally        substituted lower alkylene, —O-(alk)_(b)-, —S-(alk)_(b)-,        —NR¹⁴-(alk)_(b)-, —C(O)-(alk)_(b)-, —C(S)-(alk)_(b)-,        —S(O)-(alk)_(b)-, —S(O)₂-(alk)_(b)-, —NR¹⁴C(O)-(alk)_(b)-,        —C(O)NR¹⁴-(alk)_(b)-, S(O)₂NR¹⁴-(alk)_(b)-,        —NR¹⁴S(O)₂-(alk)_(b)-, —NR¹⁴C(O)NR¹⁴-(alk)_(b)-,        —NR¹⁴C(S)NR¹⁴-(alk)_(b)-, and —NR¹⁴S(O)₂NR¹⁴-(alk)_(b)-;    -   alk is optionally substituted C₁₋₃ alkylene;    -   b is 0 or 1; and    -   R¹⁴ is hydrogen or lower alkyl.

In another embodiment of compounds of Formula Ia, R², R⁵ and R⁶ arehydrogen, further wherein R⁴ is other than hydrogen. In anotherembodiment, R², R⁴ and R⁶ are hydrogen, further wherein R⁵ is other thanhydrogen.

In particular embodiments the compound of Formula I has a structureaccording to the following sub-generic structure, Formula Ib,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   V and W are independently selected from the group consisting of        N and CH;    -   U and Z are independently selected from the group consisting of        N and CR¹⁸, provided, however, that not more than one of W, U        and Z is N;    -   A is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S(O)—, —S(O)₂—, —NR²¹—, and —O—;    -   n is 0 or 1;    -   F and J are both C or one of F and J is C and the other of F and        J is N;    -   E and K are selected from C, N, O or S;    -   G is selected from C or N;        -   wherein            -   when n is 1, F and J are C, and E, G and K are C, or any                one of E, G and K is N and the other two of E, G and K                are C, provided that when E, G or K is N, R¹⁵, R¹⁷ and                R¹⁶, respectively, are absent,            -   when n is 0 and F and J are both C, then one of E and K                is C or N and the other of E and K is C, N, O or S,                provided both E and K are not C, and provided that when                both E and K are N, one of R¹⁵ and R¹⁶ is absent, and                provided that when one of E and K are N and the other is                O or S, R¹⁵ and R¹⁶ are absent,            -   when n is 0, one of F and J is N and the other of F and                J is C, then one of E and K is N and the other of E and                K is C, or both E and K are C, provided that when E is                N, R¹⁵ is absent and when K is N, R¹⁶ is absent;    -   R¹ is selected from the group consisting of optionally        substituted lower alkyl, optionally substituted cycloalkyl,        optionally substituted heterocycloalkyl, optionally substituted        aryl and optionally substituted heteroaryl;    -   R¹⁵ is selected from the group consisting of hydrogen,        optionally substituted lower alkyl, —OR²², —SR²² and halogen        when E is C, is absent when E is O or S or when n=1 and E is N,        and is absent or selected from the group consisting of hydrogen        and optionally substituted lower alkyl when n=0 and E is N;    -   R¹⁶ is selected from the group consisting of hydrogen,        optionally substituted lower alkyl, —OR²², —SR²² and halogen        when K is C, is absent when K is O or S or when n=1 and K is N,        and is absent or selected from the group consisting of hydrogen        and optionally substituted lower alkyl when n=0 and K is N;    -   R¹⁷ is selected from the group consisting of hydrogen,        optionally substituted lower alkyl, —OR²², —SR²² and halogen        when G is C, or is absent when G is N;    -   R¹⁸ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted aryl,        optionally substituted heteroaryl, —OH, —NH₂, —NO₂, —CN,        —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —NR²⁴R²⁵, —NHR²³, —OR²³,        —SR²³, —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³,        —NHS(O)₂R²³, —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂,        —NR²³C(O)NHR²³, —NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³,        —NR²³C(S)NH₂, NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³,        —NHS(O)₂NHR²³, —NR²³S(O)₂NH₂, —NR²³S(O)₂NHR²³, —NHS(O)₂NR²³R²³,        and —NR²³S(O)₂NR²³R²³;    -   M is selected from the group consisting of a bond,        —(CR¹⁹R²⁰)_(u)—,        -   —(CR¹⁹R²⁰)_(t)—C(O)—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—C(S)—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—C(O)O—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—C(S)O—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—C(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—S(O)—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—S(O)₂—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—S(O)₂NR²⁶—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—O—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—OC(O)—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—OC(S)—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—OC(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—OC(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—S—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)R_(s)—,            —(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—NR²⁶C(S)—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—NR²⁶C(O)O—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—NR²⁶C(S)O—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—NR²⁶C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—NR²⁶C(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,            —(CR¹⁹R²⁰)_(t)—NR²⁶S(O)₂—(CR¹⁹R²⁰)_(s)—, and            —(CR¹⁹R²⁰)_(t)—NR²⁶S(O)₂NR²⁶—(CR¹⁹R²⁰)_(s)—;    -   wherein R¹⁹ and R²⁰ at each occurrence are independently        selected from the group consisting of hydrogen, fluoro, —OH,        —NH₂, lower alkyl, lower alkoxy, lower alklylthio,        mono-alkylamino, di-alkylamino, and —NR²⁷R²⁸, wherein the alkyl        chain(s) of lower alkyl, lower alkoxy, lower alkylthio,        mono-alkylamino, or di-alkylamino are optionally substituted        with one or more substituents selected from the group consisting        of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, di-alkylamino, and cycloalkylamino; or    -   any two of R¹⁹ and R²⁰ on the same or different carbons combine        to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered        monocyclic heterocycloalkyl and any others of R¹⁹ and R²⁰ are        independently selected from the group consisting of hydrogen,        fluoro, —OH, —NH₂, lower alkyl, lower alkoxy, lower alklylthio,        mono-alkylamino, di-alkylamino, and —NR²⁷R²⁸, wherein the alkyl        chain(s) of lower alkyl, lower alkoxy, lower alkylthio,        mono-alkylamino, or di-alkylamino are optionally substituted        with one or more substituents selected from the group consisting        of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein        the monocyclic cycloalkyl or monocyclic heterocycloalkyl are        optionally substituted with one or more substituents selected        from the group consisting of halogen, —OH, —NH₂, lower alkyl,        fluoro substituted lower alkyl, lower alkoxy, fluoro substituted        lower alkoxy, lower alkylthio, fluoro substituted lower        alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;    -   R²¹ and R²² at each occurrence are independently hydrogen or        optionally substituted lower alkyl;    -   R²³ at each occurrence is independently selected from the group        consisting of optionally substituted lower alkyl, optionally        substituted lower alkenyl, provided, however, that no alkene        carbon thereof is bound to any —C(O)—, —C(S)—, —S(O)₂—, —O—,        —S—, or —N— of any of —NHR²³, —OR²³, —SR²³, —NHC(O)R²³,        —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³, —NHS(O)₂R²³,        —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,        —NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,        —NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,        —NR²³S(O)₂NH₂, —NR²³S(O)₂NHR²³, —NHS(O)₂NR²³R²³, or        —NR²³S(O)₂NR²³R²³, optionally substituted lower alkynyl,        provided, however, that no alkyne carbon thereof is bound to any        —C(O)—, —C(S)—, —S(O)—, —S(O)₂—, —O—, —S—, or —N— of any of        —NHR²³, —OR²³, —SR²³, —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³,        —NR²³C(S)R²³, —NHS(O)₂R²³, —NR²³S(O)₂R²³, —NHC(O)NHR²³,        —NR²³C(O)NH₂, —NR²³C(O)NHR²³, —NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³,        —NHC(S)NHR²³, —NR²³C(S)NH₂, —NR²³C(S)NHR²³, —NHC(S)NR²³R²³,        —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³, —NR²³S(O)₂NH₂, —NR²³S(O)₂NHR²³,        —NHS(O)₂NR²³R²³, or —NR²³S(O)₂NR²³R²³, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, and optionally substituted heteroaryl;    -   R²⁴ and R²⁵ at each occurrence are independently selected from        the group consisting of optionally substituted lower alkyl,        optionally substituted lower alkenyl, provided, however, that no        alkene carbon thereof is bound to the nitrogen of —NR²⁴R²⁵,        optionally substituted lower alkynyl, provided, however, that no        alkyne carbon thereof is bound to the nitrogen of —NR²⁴R²⁵,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl, and optionally        substituted heteroaryl; or    -   R²⁴ and R²⁵ together with the nitrogen to which they are        attached form a monocyclic 5-7 membered optionally substituted        heterocycloalkyl or a monocyclic 5 or 7 membered optionally        substituted nitrogen containing heteroaryl;    -   R²⁶ at each occurrence is independently selected from the group        consisting of hydrogen, lower alkyl, and lower alkyl substituted        with one or more substituents selected from the group consisting        of fluoro, —OH, —NH₂, lower alkoxy, fluoro substituted lower        alkoxy, lower alkylthio, fluoro substituted lower alkylthio,        mono-alkylamino, fluoro substituted mono-alkylamino,        di-alkylamino, fluoro substituted di-alkylamino, and —NR²⁷R²⁸,        provided, however, that when R²⁶ is substituted lower alkyl, any        substitution on the lower alkyl carbon bound to the —N— of        —NR²⁶— is fluoro;    -   R²⁷ and R²⁸ combine with the nitrogen to which they are attached        to form a 5-7 membered heterocycloalkyl or 5-7 membered        heterocycloalkyl substituted with one or more substituents        selected from the group consisting of fluoro, —OH, —NH₂, lower        alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro        substituted lower alkoxy, lower alkylthio, and fluoro        substituted lower alkylthio;    -   u is 1-6;    -   t is 0-3; and    -   s is 0-3;    -   provided that        -   when V, W, U and Z are CH, n=1, E, F, G, J, and K are C,            R¹⁵, R¹⁶ and R¹⁷ are H, A is —CH₂—, —CH(OH)—, or —C(O)—, and            M is —NHCH₂—, then R¹ is not phenyl,            4-trifluoromethyl-phenyl, 4-methoxy-phenyl, 4-chloro-phenyl,            4-fluoro-phenyl, 4-methyl-phenyl, 3-fluoro-phenyl or            thiophen-2-yl,        -   when V, W, U and Z are CH, n=1, E, F, G, J, and K are C,            R¹⁵, R¹⁶ and R¹⁷ are H, and A is —CH₂—, then M-R¹ is not            —NHCH₂CH(CH₃)₂,        -   when V, W, and U are CH, n=1, E, F, G, J, and K are C, R¹⁵,            R¹⁶ and R¹⁷ are H, A is —CH₂—, M-R¹ is —OCH₃, and Z is CR¹⁸,            then R¹⁸ is not thiophen-3-yl, and        -   when V, W, and U are CH, n=0, F, J, and K are C, E is N, R¹⁵            is CH₃, R¹⁶ is H, A is —C(O)—, M-R¹ is —CH(CH₃)₃, and Z is            CR¹⁸, then R¹⁸ is not 3-((E)-2-carboxy-vinyl)phenyl.

In one embodiment of the compounds of Formula Ib, E, J, K, G, F, n, R¹⁵,R¹⁶ and R¹⁷ are selected to provide structures selected from the groupconsisting of

wherein R¹⁵, R¹⁶ and R¹⁷ are as defined for compounds of Formula Ib andwherein

indicates the point of attachment of A and

indicates the point of attachment of M.

In one embodiment of compounds of Formula Ib, M is selected from thegroup consisting of —O—(CR¹⁹R²⁰)_(s)—, —S—(CR¹⁹R²⁰)_(s)—,—OC(O)—(CR¹⁹R²⁰)_(s)—, —OC(S)—(CR¹⁹R²⁰)_(s)—, —OC(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,—OC(S)NR²⁶—(CR¹⁹R²⁰)_(s)—, —C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,—C(S)NR²⁶—(CR¹⁹R²⁰)_(s)—, —S(O)₂NR²⁶—(CR¹⁹R²⁰)_(s)—,—NR²⁶—(CR¹⁹R²⁰)_(s)—, —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—,—NR²⁶C(S)—(CR¹⁹R²⁰)_(s)—, —NR²⁶C(O)O—(CR¹⁹R²⁰)_(s)—,—NR²⁶C(S)O—(CR¹⁹R²⁰)_(s)—, —NR²⁶C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,—NR²⁶C(S)NR²⁶—(CR¹⁹R²⁰)_(s)—, —NR²⁶S(O)₂—(CR¹⁹R²⁰)_(s)—, and—NR²⁶S(O)₂NR²⁶—(CR¹⁹R²⁰)_(s)—.

In one embodiment of compounds of Formula Ib, R²⁶ at each occurrence isindependently selected from the group consisting of hydrogen, loweralkyl, and lower alkyl substituted with 1, 2, or 3 substituents selectedfrom the group consisting of fluoro, —OH, —NH₂, alkoxy, lower alkylthio,mono-alkylamino, di-alkylamino and cycloalkylamino, provided that anysubstitution on the carbon that is bound to the nitrogen of —NR²⁶ isfluoro.

In one embodiment of compounds of Formula Ib, R¹ is selected from thegroup consisting of optionally substituted aryl and optionallysubstituted heteroaryl.

In one embodiment of the compounds of Formula Ib, Z is N or CH, n is 1,E-R¹⁵ is N or CH, K—R¹⁶ is N or CH, and G-R¹⁷ is N or CH, provided nomore than one of E-R¹⁵, K—R¹⁶ and G-R¹⁷ is N. In one embodiment, Z is Nor CH, n is 1, and E-R¹⁵, K—R¹⁶ and G-R¹⁷ are CH.

In one embodiment of the compounds of Formula Ib, V, W and Z are CH, Uis CR¹⁸, n is 1, E-R¹⁵ is N or CH, K—R¹⁶ is N or CH, and G-R¹⁷ is N orCH, provided no more than one of E-R¹⁵, K—R¹⁶ and G-R¹⁷ is N. In anotherembodiment, V, W and Z are CH, U is CR¹⁸, n is 1, and E-R¹⁵, K—R¹⁶ andG-R¹⁷ are CH.

In one embodiment of the compounds of Formula Ib, Z is N or CH, n is 1,E-R¹⁵, K—R¹⁶ and G-R¹⁷ are CH, A is —CH₂—, M is —NHCH₂—, further whereinR¹ is optionally substituted phenyl. In another embodiment, V, Z, U andW are CH, n is 1, E-R¹⁵ is N or CH, K—R¹⁶ is N or CH, and G-R¹⁷ is N orCH, provided no more than one of E-R¹⁵, K—R¹⁶ and G-R¹⁷ is N.

In one embodiment of the compounds of Formula Ib, Z is N or CH, n is 1,E-R¹⁵ is N or CH, K—R¹⁶ is N or CH, and G-R¹⁷ is N or CH, provided nomore than one of E-R¹⁵, K—R¹⁶ and G-R¹⁷ is N, and R¹ is phenyloptionally substituted with one or more substituents selected from thegroup consisting of halogen, —OH, —NH₂, —NO₂, —CN, optionallysubstituted lower alkyl and —OR²⁹, where R²⁹ is selected from the groupconsisting of optionally substituted lower alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl and optionally substituted heteroaryl.

In one embodiment of the compounds of Formula Ib, V, Z, U and W are CH,n is 1, E-R¹⁵, K—R¹⁶ and G-R¹⁷ are CH, A is —CH₂—, M is —NHCH₂, and R¹is optionally substituted phenyl, further wherein R¹ is phenyloptionally substituted with one or more substituents selected from thegroup consisting of halogen, —OH, —NH₂, —NO₂, —CN, optionallysubstituted lower alkyl and —OR²⁹, where R²⁹ is selected from the groupconsisting of optionally substituted lower alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl and optionally substituted heteroaryl.

In one embodiment of the compounds of Formula Ib, V, W and Z are CH, Uis CR¹⁸, n is 1, E-R¹⁵, K—R¹⁶ and G-R¹⁷ are CH, A is —CH₂—, M is —NHCH₂,and R¹ is optionally substituted phenyl, further wherein R¹ is phenyloptionally substituted with one or more substituents selected from thegroup consisting of halogen, —OH, —NH₂, —NO₂, —CN, optionallysubstituted lower alkyl and —OR²⁹, where R²⁹ is selected from the groupconsisting of optionally substituted lower alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl and optionally substituted heteroaryl.

In one embodiment of the compounds of Formula Ib, when n is 1, and E, Kand G are C, at least one of R¹⁵, R¹⁶ and R¹⁷ is other than hydrogen. Inanother embodiment, n is 1, one of E, K, and G are N and the other twoof E, K, and G are C and at least one of R¹⁵, R¹⁶ and R¹⁷ is other thanhydrogen. In another embodiment, n is 1, E, K and G are C, and at leastone of R¹⁵, R¹⁶ and R¹⁷ is other than hydrogen.

In one embodiment of the compounds of Formula Ib, n is 1, V and W areCH, U and Z are independently CR¹⁸, one of E, K, and G are N and theother two of E, K, and G are C and at least one of R¹⁵, R¹⁶ and R¹⁷ isother than hydrogen. In another embodiment, n is 1, V and W are CH, Uand Z are independently CR¹⁸, E, K and G are C, and at least one of R¹⁵,R¹⁶ and R¹⁷ is other than hydrogen.

In one embodiment of the compounds of Formula Ib, n is 1, one of E, K,and G are N and the other two of E, K, and G are C, at least one of R¹⁵,R¹⁶ and R¹⁷ is other than hydrogen, A is —CH₂—, M is —NHCH₂—, furtherwherein R¹ is optionally substituted phenyl. In another embodiment, n is1, E, K, and G are C, at least one of R¹⁵, R¹⁶ and R¹⁷ is other thanhydrogen, A is —CH₂—, M is —NHCH₂—, further wherein R¹ is optionallysubstituted phenyl.

In one embodiment of the compounds of Formula Ib, n is 1, V, Z, U and Ware CH, one of E, K, and G are N and the other two of E, K, and G are Cand at least one of R¹⁵, R¹⁶ and R¹⁷ is other than hydrogen. In anotherembodiment, V, Z, U and W are CH, E, K and G are C, and at least one ofR¹⁵, R¹⁶ and R¹⁷ is other than hydrogen.

In one embodiment of the compounds of Formula Ib, Z is CR¹⁸, wherein R¹⁸is other than hydrogen, n is 1, E-R¹⁵ is N or CH, K—R¹⁶ is N or CH andG-R¹⁷ is N or CH. In another embodiment, Z is CR¹⁸, wherein R¹⁸ is otherthan hydrogen, n is 1, and E-R¹⁵, K—R¹⁶ and G-R¹⁷ are CH. In anotherembodiment, Z is CR¹⁸, wherein R¹⁸ is other than hydrogen, U is CR¹⁸, Vand W are CH, n is 1, and E-R¹⁵, K—R¹⁶ and G-R¹⁷ are CH, further whereinU is CH.

In one embodiment of the compounds of Formula Ib, Z is CR¹⁸, wherein R¹⁸is other than hydrogen, n is 1, E-R¹⁵, K—R¹⁶ and G-R¹⁷ are CH, A is—CH₂—, M is —NHCH₂—, further wherein R¹ is optionally substitutedphenyl. In a further embodiment, Z is CR¹⁸, wherein R¹⁸ is other thanhydrogen, U is CR¹⁸, V and W are CH, n is 1, E-R¹⁵, K—R¹⁶ and G-R¹⁷ areCH, A is —CH₂—, M is —NHCH₂—, further wherein R¹ is optionallysubstituted phenyl. In a further embodiment, Z is CR¹⁸, wherein R¹⁸ isother than hydrogen, V, U and W are CH, n is 1, E-R¹⁵, K—R¹⁶ and G-R¹⁷are CH, A is —CH₂—, M is —NHCH₂—, further wherein R¹ is optionallysubstituted phenyl.

In one embodiment of the compounds of Formula Ib, U is CR¹⁸, wherein R¹⁸is other than hydrogen, n is 1, E-R¹⁵ is N or CH, K—R¹⁶ is N or CH andG-R¹⁷ is N or CH. In another embodiment, U is CR¹⁸, wherein R¹⁸ is otherthan hydrogen, n is 1, and E-R¹⁵, K—R¹⁶ and G-R¹⁷ are CH. In anotherembodiment, U is CR¹⁸, wherein R¹⁸ is other than hydrogen, Z is CR¹⁸, Vand W are CH, n is 1, and E-R¹⁵, K—R¹⁶ and G-R¹⁷ are CH, further whereinZ is CH.

In one embodiment of the compounds of Formula Ib, U is CR¹⁸, wherein R¹⁸is other than hydrogen, n is 1, E-R¹⁵, K—R¹⁶ and G-R¹⁷ are CH, A is—CH₂—, M is —NHCH₂—, further wherein R¹ is optionally substitutedphenyl. In a further embodiment, U is CR¹⁸, wherein R¹⁸ is other thanhydrogen, Z is CR¹⁸, V and W are CH, n is 1, E-R¹⁵, K—R¹⁶ and G-R¹⁷ areCH, A is —CH₂—, M is —NHCH₂—, further wherein R¹ is optionallysubstituted phenyl. In a further embodiment, U is CR¹⁸, wherein R¹⁸ isother than hydrogen, V, Z and W are CH, n is 1, E-R¹⁵, K—R¹⁶ and G-R¹⁷are CH, A is —CH₂—, M is —NHCH₂—, further wherein R¹ is optionallysubstituted phenyl.

In one embodiment of the compounds of Formula Ib, further to any of theabove embodiments, R¹⁵, R¹⁶ and R¹⁷ are independently selected from thegroup consisting of halogen, —OH, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, and fluoro substituted lower alkoxy. Further to anyof these embodiments R¹ is phenyl optionally substituted with one ormore substituents selected from the group consisting of halogen, —OH,—NH₂, —NO₂, —CN, optionally substituted lower alkyl and —OR²⁹, where R²⁹is selected from the group consisting of optionally substituted loweralkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl and optionally substitutedheteroaryl.

In one embodiment of the compounds of Formula Ib, further to any of theabove embodiments, R¹⁸ is selected from the group consisting of halogen,—OH, optionally substituted lower alkyl and —OR²⁹, where R²⁹ is selectedfrom the group consisting of optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl and optionally substitutedheteroaryl. Further to any of these embodiments, R¹ is phenyl optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, —OH, —NH₂, —NO₂, —CN, optionally substitutedlower alkyl and —OR²⁹, where R²⁹ is selected from the group consistingof optionally substituted lower alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl and optionally substituted heteroaryl.

In another embodiment of compounds of Formula Ib, M is a bond and R¹ isother than thiophenyl.

In another embodiment of the compounds of Formula Ib, Z is N or CR¹⁸wherein R¹⁸ is not hydrogen. Further to this embodiment, as allowed inthe description of Formula Ib, E is NR¹⁵ or CR¹⁵, K is NR¹⁶ or CR¹⁶ andG is CR¹⁷, or combinations thereof, wherein at least one of R¹⁵, R¹⁶ andR¹⁷ is not hydrogen.

In one embodiment, a compound of Formula I has a structure according tothe following sub-generic structure, Formula Ig,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   Z₁ is selected from the group consisting of N and CR³⁴;    -   U₁ is selected from the group consisting of N and CR³⁵;    -   A₁ is selected from the group consisting of —CH₂— and —C(O)—;    -   M₃ is selected from the group consisting of a bond, —NR³⁹—, —S—,        —O—, —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, —C(O)NR³⁹—,        —S(O)₂NR³⁹—, —CH₂NR³⁹—, —CH(R⁴⁰)NR³⁹—, —NR³⁹C(O)—, and        —NR³⁹S(O)₂—;    -   n is 0 or 1;    -   v is 0, 1, 2 or 3;    -   F₁ and J₁ are both C or one of F₁ and J₁ is C and the other of        F₁ and J₁ is N;    -   E₁ and K₁ are independently selected from C, N, O or S;    -   G₁ is selected from C or N;        -   wherein            -   when n is 1, F₁ and J₁ are C, and E₁, G₁ and K₁ are C,                or any one of E₁, G₁ and K₁ is N and the other two of                E₁, G₁ and K₁ are C, provided that when E₁, G₁ or K₁ is                N, R³⁶, R³⁷ and R³⁸, respectively, are absent;            -   when n is 0 and F₁ and J₁ are both C, then one of E₁ and                K₁ is C or N and the other of E₁ and K₁ is C, N, O or S,                provided both E₁ and K₁ are not C, and provided that                when both E₁ and K₁ are N, one of R³⁶ and R³⁷ is absent,                and provided that when one of E₁ and K₁ are N and the                other is O or S, R³⁶ and R³⁷ are absent;            -   when n is 0, one of F₁ and J₁ is N and the other of F₁                and J₁ is C, then one of E₁ and K₁ is N and the other of                E₁ and K₁ is C, or both E₁ and K₁ are C, provided that                when E₁ is N, R³⁶ is absent and when K₁ is N, R³⁷ is                absent;    -   Cy is selected from the group consisting of cycloalkyl,        heterocycloalkyl, aryl and heteroaryl;    -   R³⁴ and R³⁵ are independently selected from the group consisting        of hydrogen, —OR⁴¹, —SR⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹,        —NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,        heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is        optionally substituted with one or more substituents selected        from the group consisting of fluoro, lower alkoxy, fluoro        substituted lower alkoxy, lower alkylthio, fluoro substituted        lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl as R³⁴ or R³⁵, or as        substituents of lower alkyl are optionally substituted with one        or more substituents selected from the group consisting of —OH,        —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴², —NHR⁴²,        —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, lower        alkyl, fluoro substituted lower alkyl, and cycloalkylamino;    -   R⁴⁵ at each occurrence is independently selected from the group        consisting of —OR⁴¹, —SR⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹,        —NR³⁹S(O)₂R⁴¹, K halogen, lower alkyl, cycloalkyl,        heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is        optionally substituted with one or more substituents selected        from the group consisting of fluoro, lower alkoxy, fluoro        substituted lower alkoxy, lower alkylthio, fluoro substituted        lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl as R⁴⁵, or as        substituents of lower alkyl are optionally substituted with one        or more substituents selected from the group consisting of —OH,        —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴², —NHR⁴²,        —NR⁴²R⁴², —NR³⁹C(O)₂R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen,        lower alkyl, fluoro substituted lower alkyl, and        cycloalkylamino;    -   R³⁶ is selected from the group consisting of hydrogen, halogen,        lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and        fluoro substituted lower alkoxy when E₁ is C, is absent when E₁        is O or S or when n=1 and E₁ is N, and is absent or selected        from the group consisting of hydrogen, lower alkyl, and fluoro        substituted lower alkyl when n=0 and E₁ is N;    -   R³⁷ is selected from the group consisting of hydrogen, halogen,        lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and        fluoro substituted lower alkoxy when K₁ is C, is absent when K₁        is O or S or when n=1 and K₁ is N, and is absent or selected        from the group consisting of hydrogen, lower alkyl, and fluoro        substituted lower alkyl when n=0 and K₁ is N;    -   R³⁸ is selected from the group consisting of hydrogen, halogen,        lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and        fluoro substituted lower alkoxy when G₁ is C, or is absent when        G₁ is N;    -   R³⁹ at each occurrence is independently hydrogen or lower alkyl;    -   R⁴⁰ is lower alkyl or fluoro substituted lower alkyl;    -   R⁴¹ is selected from the group consisting of lower alkyl,        cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower        alkyl is optionally substituted with one or more substituents        selected from the group consisting of fluoro, lower alkoxy,        fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R⁴¹ or as        substituents of lower alkyl are optionally substituted with one        or more substituents selected from the group consisting of —OH,        —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴², —NHR⁴²,        —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, lower        alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and    -   R⁴² at each occurrence is independently selected from the group        consisting of lower alkyl, heterocycloalkyl and heteroaryl,        wherein lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, lower        alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino, and        cycloalkylamino, and heterocycloalkyl and heteroaryl are        optionally substituted with one or more substituents selected        from the group consisting of halogen, —CN, lower alkyl, fluoro        substituted lower alkyl, lower alkoxy and fluoro substituted        lower alkoxy.

In one embodiment of compounds of Formula Ig, n is 1, G₁ and K₁ are C,and E is N or C, preferably wherein E is C.

In one embodiment of compounds of Formula Ig, M₃ is selected from thegroup consisting of —NR³⁹—, —O—, —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—,—OCH₂—, —CH₂NR³⁹—, —NR³⁹C(O)—, and —NR³⁹S(O)₂—, preferably wherein M₃ is—NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, or —CH₂NR³⁹—.

In one embodiment of compounds of Formula Ig, n is 1, G₁ and K₁ are C,and E is N or C, preferably wherein E is C, and M₃ is selected from thegroup consisting of —NR³⁹—, —O—, —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—,—OCH₂—, —CH₂NR³⁹—, —NR³⁹C(O)—, and —NR³⁹S(O)₂—, preferably wherein M₃ is—NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, or —CH₂NR³⁹—.

In one embodiment of compounds of Formula Ig, each R⁴⁵ is selected fromthe group consisting of —OH, —NH₂, —CN, —NO₂, halogen, lower alkyl,fluoro substituted lower alkyl, lower alkoxy, fluoro substituted loweralkoxy, lower thioalkyl, fluoro substituted lower thioalkyl,mono-alkylamino, di-alkylamino and cycloalkylamino, preferably wherein vis 0, 1, or 2, also 0 or 1.

In one embodiment of compounds of Formula Ig, n is 1, G₁ and K₁ are C,and E is N or C, preferably wherein E is C, M₃ is selected from thegroup consisting of —NR³⁹—, —O—, —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—,—OCH₂—, —CH₂NR³⁹—, —NR³⁹C(O)—, and —NR³⁹S(O)₂, preferably wherein M₃ is—NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, or —CH₂NR³⁹—, and each R⁴⁵ isselected from the group consisting of —OH, —NH₂, —CN, —NO₂, halogen,lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluorosubstituted lower alkoxy, lower thioalkyl, fluoro substituted lowerthioalkyl, mono-alkylamino, di-alkylamino and cycloalkylamino,preferably wherein v is 0, 1, or 2, also 0 or 1.

In one embodiment of compounds of Formula Ig, Z₁ is CR³⁴, U₁ is CR³⁵,and R³⁴ and R³⁵ are both hydrogen. In one embodiment, Z₁ is CR³⁴, U₁ isCR³⁵, and R³⁴ and R³⁵ are independently selected from the groupconsisting of hydrogen, —OR⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl and heteroaryl are optionally substituted withone or more substituents selected from the group consisting of —OH,—NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴², —NHR⁴², —NR⁴²R⁴²,NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, lower alkyl, fluorosubstituted lower alkyl, and cycloalkylamino, and wherein lower alkyl isoptionally substituted with one or more substituents selected from thegroup consisting of fluoro, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino, and cycloalkylamino. In a furtherembodiment, one of R³⁴ and R³⁵ is hydrogen, and the other of R³⁴ and R³⁵is selected from the group consisting of hydrogen, halogen, lower alkyl,lower alkoxy, aryl and heteroaryl, wherein aryl and heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴²,—SR⁴², —NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴²,halogen, lower alkyl, fluoro substituted lower alkyl, andcycloalkylamino, and wherein lower alkyl and lower alkoxy are optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, and cycloalkylamino, further wherein the other of R³⁴ andR³⁵ is selected from the group consisting of halogen, lower alkyl, andlower alkoxy, wherein lower alkyl and lower alkoxy are optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, and cycloalkylamino.

In one embodiment of compounds of Formula Ig, each R⁴⁵ is independentlyselected from the group consisting of —OH, —NH₂, —CN, —NO₂, halogen,lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluorosubstituted lower alkoxy, lower thioalkyl, fluoro substituted lowerthioalkyl, mono-alkylamino, di-alkylamino and cycloalkylamino,preferably wherein v is 0, 1, or 2, also 0 or 1, Z₁ is CR³⁴, U₁ is CR³⁵,and R³⁴ and R³⁵ are independently selected from the group consisting ofhydrogen, —OR⁴¹, halogen, lower alkyl, cycloalkyl, heterocycloalkyl,aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl andheteroaryl are optionally substituted with one or more substituentsselected from the group consisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂,—C(O)NH₂, —OR⁴², —SR⁴², —NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴²,—S(O)₂R⁴², halogen, lower alkyl, fluoro substituted lower alkyl, andcycloalkylamino, and wherein lower alkyl is optionally substituted withone or more substituents selected from the group consisting of fluoro,lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluorosubstituted lower alkylthio, mono-alkylamino, di-alkylamino, andcycloalkylamino. In a further embodiment, both of R³⁴ and R³⁵ arehydrogen.

In one embodiment of compounds of Formula Ig, each R⁴⁵ is selected fromthe group consisting of —OH, —NH₂, —CN, —NO₂, halogen, lower alkyl,fluoro substituted lower alkyl, lower alkoxy, fluoro substituted loweralkoxy, lower thioalkyl, fluoro substituted lower thioalkyl,mono-alkylamino, di-alkylamino and cycloalkylamino, preferably wherein vis 0, 1, or 2, also 0 or 1, Z₁ is CR³⁴, U₁ is CR³⁵, one of R³⁴ and R³⁵is hydrogen, and the other of R³⁴ and R³⁵ is selected from the groupconsisting of hydrogen, halogen, lower alkyl, lower alkoxy, aryl andheteroaryl, wherein aryl and heteroaryl are optionally substituted withone or more substituents selected from the group consisting of —OH,—NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴², —NHR⁴², —NR⁴²R⁴²,—NR³⁹C(O)R⁴², —S(O)₂R⁴², —S(O)₂R⁴², halogen, lower alkyl, fluorosubstituted lower alkyl, and cycloalkylamino, and wherein lower alkyland lower alkoxy are optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, fluoro substitutedlower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino,further wherein the other of R³⁴ and R³⁵ is selected from the groupconsisting of halogen, lower alkyl, and lower alkoxy, wherein loweralkyl and lower alkoxy are optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, fluoro substitutedlower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.

In one embodiment of compounds of Formula Ig, n is 1, G₁ and K₁ are C,and E is N or C, preferably wherein E is C, M₃ is selected from thegroup consisting of —NR³⁹—, —O—, —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—,—OCH₂—, —CH₂NR³⁹—, —NR³⁹C(O)—, and —NR³⁹S(O)₂, preferably wherein M₃ is—NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, or —CH₂NR³⁹—, each R⁴⁵ isselected from the group consisting of —OH, —NH₂, —CN, —NO₂, halogen,lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluorosubstituted lower alkoxy, lower thioalkyl, fluoro substituted lowerthioalkyl, mono-alkylamino, di-alkylamino and cycloalkylamino,preferably wherein v is 0, 1, or 2, also 0 or 1, Z₁ is CR³⁴, U₁ is CR³⁵,and R³⁴ and R³⁵ are both hydrogen.

In one embodiment of compounds of Formula Ig, n is 1, G₁ and K₁ are C,and E is N or C, preferably wherein E is C, M₃ is selected from thegroup consisting of —NR³⁹—, —O—, —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—,—OCH₂—, —CH₂NR³⁹—, —NR³⁹C(O)—, and —NR³⁹S(O)₂, preferably wherein M₃ is—NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, or —CH₂NR³⁹—, each R⁴⁵ isselected from the group consisting of —OH, —NH₂, —CN, —NO₂, halogen,lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluorosubstituted lower alkoxy, lower thioalkyl, fluoro substituted lowerthioalkyl, mono-alkylamino, di-alkylamino and cycloalkylamino,preferably wherein v is 0, 1, or 2, also 0 or 1, Z₁ is CR³⁴ and U₁ isCR³⁵, and R³⁴ and R³⁵ are independently selected from the groupconsisting of hydrogen, —OR⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl and heteroaryl are optionally substituted withone or more substituents selected from the group consisting of —OH,—NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴², —NHR⁴², —NR⁴²R⁴²,—NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, lower alkyl, fluorosubstituted lower alkyl, and cycloalkylamino, and wherein lower alkyl isoptionally substituted with one or more substituents selected from thegroup consisting of fluoro, lower alkoxy, fluoro substituted loweralkoxy, lower alkylthio, fluoro substituted lower alkylthio,mono-alkylamino, di-alkylamino, and cycloalkylamino. In a furtherembodiment, one of R³⁴ and R³⁵ is hydrogen, and the other of R³⁴ and R³⁵is selected from the group consisting of halogen, lower alkyl, loweralkoxy, aryl and heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino, and whereinlower alkyl and lower alkoxy are optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, fluoro substitutedlower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino,further wherein the other of R³⁴ and R³⁵ is selected from the groupconsisting of halogen, lower alkyl, and lower alkoxy, wherein loweralkyl and lower alkoxy are optionally substituted with one or moresubstituents selected from the group consisting of fluoro, lower alkoxy,fluoro substituted lower alkoxy, lower alkylthio, fluoro substitutedlower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino,further wherein R³⁴ is hydrogen.

In one embodiment, a compound of Formula I has a structure according tothe following sub-generic structure, Formula II,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   D has a structure selected from the group consisting of

in which

indicates the attachment point of D to A₂ of Formula II;

-   -   A₂ is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S(O)—, —S(O)₂—, —NR²¹—, and —O—, provided,        however, that when A₂ is NR²¹, N is not bound to a nitrogen of        D;    -   B is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —NH₂,        —NO₂, —CN, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(O)NH₂,        —C(S)NH₂, —S(O)₂NH₂, —NR²⁴R²⁵, —NHR²³, —OR²³, —SR²³, —C(O)R²³,        —C(S)R²³, —S(O)R²³, —S(O)₂R²³, —C(O)NHR²³, —C(O)NR²³R²³,        —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³, —S(O)₂NR²³R²³,        —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³, —NHS(O)₂R²³,        —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,        —NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,        —NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,        —NR²³S(O)₂NH₂, —NR²³S(O)₂NHR²³, —NHS(O)₂NR²³R²³, and        —NR²³S(O)₂NR²³R²³;    -   M₄ is —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)—, —NR³⁹CH₂CH₂—, or —NR³⁹C(O)—;    -   M₅, M₆, M₇, M₉, M₁₀, M₁₁, M₁₂, M₁₃, M₁₄, M₁₅ M₁₆, M₁₇ and M₁₈        are selected from the group consisting of a bond,        —(CR¹⁹R²⁰)_(u)—, —(CR¹⁹R²⁰)_(t)—C(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(S)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(O)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(S)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—S(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—S(O)₂—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—S(O)₂NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—OC(S)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—OC(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—OC(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—S—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶C(S)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶C(O)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶C(S)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶C(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶S(O)₂—(CR¹⁹R²⁰)_(s)—, and        —(CR¹⁹R²⁹)_(t)—NR²⁶S(O)₂NR²⁶—(CR¹⁹R²⁰)_(s)—;    -   M₈ is selected from the group consisting of a bond,        —(CR¹⁹R²⁰)_(u)—, —(CR¹⁹R²⁰)_(t)—C(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(S)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(r)—C(O)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(S)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,        (CR¹⁹R²⁰)_(t)—S(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—S(O)₂—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—S(O)₂NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—O—(CR¹⁹R²⁰)_(s)—, —(CR¹⁹R²⁰),        —OC(O)—(CR¹⁹R²⁰)_(s)—, —(CR¹⁹R²⁰)_(w)—OC(S)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰), —OC(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—OC(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—S—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—NR²⁶C(S)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—NR²⁶C(O)O—(CR¹⁹R²⁰)_(w)—(CR¹⁹R²⁰)_(w)—NR²⁶C(S)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—NR²⁶C(O)NR²⁶—(CR¹⁹R²⁰)_(w)—(CR¹⁹R²⁰)_(w)—NR²⁶C(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—NR²⁶S(O)₂—(CR¹⁹R²⁰)_(s)—, and        —(CR¹⁹R²⁰)_(w)—NR²⁶S(O)₂NR²⁶—(CR¹⁹R²⁰)_(s)—;

Q¹ is aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHS(O)₂R⁴³, —NHC(O)R⁴³, —NHR⁴³, —NR⁴³R⁴³, —OR⁴³, SR⁴³, S(O)R⁴³, and—S(O)₂R⁴³;

-   -   Q¹¹, Q²¹, Q³¹, Q⁴¹, Q⁵¹, Q⁶¹, Q⁷¹, Q⁸¹, Q⁹¹, Q¹⁰¹, Q¹¹¹, Q¹²¹,        Q¹³¹, and Q¹⁴¹ are selected from the group consisting of        optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl and optionally substituted heteroaryl;    -   Q¹² is fluoro, chloro or —CF₃;    -   Q¹³ and Q¹⁴ are independently hydrogen, fluoro, chloro, lower        alkyl, or fluoro substituted lower alkyl;    -   Q²², Q²⁴, Q³², Q³³, Q⁴³, Q⁴⁴, Q⁵², Q⁵⁴, Q¹⁰² and Q¹⁰⁴ are        independently selected from the group consisting of hydrogen,        halogen, lower alkyl, fluoro substituted lower alkyl, —NR⁴⁴R⁴⁴,        —OR⁴⁴, and —SR⁴⁴, provided, however, that at least one of Q²²        and Q²⁴, at least one of Q³² and Q³³, at least one of Q⁴³ and        Q⁴⁴, at least one of Q⁵² and Q⁵⁴, and at least one of Q¹⁰² and        Q¹⁰⁴ is hydrogen, fluoro, chloro, lower alkyl or fluoro        substituted lower alkyl;    -   Q⁶², Q⁷⁴, Q¹¹², Q¹²⁴, Q¹³², Q¹⁴⁴, and Q¹⁵² are hydrogen, fluoro,        chloro, lower alkyl, fluoro substituted lower alkyl, —NR⁴⁴R⁴⁴,        —0R⁴⁴, or —SR⁴⁴;    -   Q⁶⁴, Q⁷², Q⁸², and Q⁹⁴ are hydrogen, lower alkyl or fluoro        substituted lower alkyl;    -   R⁴³ at each occurrence is independently optionally substituted        lower alkyl, optionally substituted cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl or        optionally substituted hetereoaryl;    -   R³⁹ and R⁴⁰ are as defined for Formula Ig;    -   each R⁴⁴ is independently hydrogen, lower alkyl or fluoro        substituted lower alkyl;    -   w is 1, 2, or 3; and    -   R¹⁹, R²⁰, R²¹, R²³, R²⁴, R²⁵, R²⁶, s, t and u are as defined for        Formula Ib;    -   provided, however, that the compound is not

In one embodiment of compounds of Formula II,

-   -   D has a structure selected from the group consisting of

in which

indicates the attachment point of D to A₂ of Formula II;

-   -   A₂ is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S(O)—, —S(O)₂—, —NR²¹—, and —O—, provided,        however, that when A₂ is NR²¹, N is not bound to a nitrogen of        D, preferably A₂ is —CH₂— or —C(O)—;    -   B is selected from the group consisting of hydrogen, —CN, —OR⁴¹,        —SR⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹,        —C(O)NR³⁹R⁴¹, —C(O)R⁴¹, —S(O)₂NR³⁹R⁴¹, —S(O)₂R⁴¹, halogen, lower        alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,        wherein lower alkyl is optionally substituted with one or more        substituents selected from the group consisting of fluoro, lower        alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro        substituted lower alkylthio, mono-alkylamino, di-alkylamino,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as B, or as        substituents of lower alkyl are optionally substituted with one        or more substituents selected from the group consisting of —OH,        —NH₂, —CN, —NO₂, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,        —NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴²,        halogen, lower alkyl, fluoro substituted lower alkyl, and        cycloalkylamino;    -   M₄ is —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)—, —NR³⁹CH₂CH₂, or —NR³⁹C(O)—,        preferably —NHCH₂— or —NHC(O)—;    -   M₅, M₁₀, and M₁₈ are selected from the group consisting of a        bond, —(CR¹⁹R²⁰)_(u)—, —(CR¹⁹R²⁰)_(t)—C(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(S)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(O)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(S)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—S(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—S(O)₂—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—S(O)₂NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—OC(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—OC(S)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—OC(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—OC(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—S—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶C(S)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶C(O)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶C(S)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶C(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—NR²⁶S(O)₂—(CR¹⁹R²⁰)_(s)—, and        —(CR¹⁹R²⁰)_(t)—NR²⁶S(O)₂NR²⁶—(CR¹⁹R²⁰)_(s)—, preferably a bond,        —NR³⁹—, —S—, —O—, —NR³⁹CH₂—, —NR³⁹CH₂CH₂—, —NR³⁹CH(R⁴⁰)—,        —SCH₂—, —OCH₂—, —C(O)NR³⁹—, —S(O)₂NR³⁹—, —CH₂NR³⁹—,        —CH(R⁴⁰)NR³⁹—, —NR³⁹C(O)—, or —NR³⁹S(O)₂—, more preferably        —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)— or —NR³⁹C(O)—, more preferably —NHCH₂—,        —NHCH(CH₃)— or —NHC(O)—;    -   M₈ is selected from the group consisting of a bond,        —(CR¹⁹R²⁰)_(u)—, —(CR¹⁹R²⁰)_(t)—C(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(S)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(O)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(S)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—C(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—S(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—S(O)₂—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(t)—S(O)₂NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—OC(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—OC(S)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—OC(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—OC(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—S—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—NR²⁶C(S)—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—NR²⁶C(O)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—NR²⁶C(S)O—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—NR²⁶C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—NR²⁶C(S)NR²⁶—(CR¹⁹R²⁰)_(s)—,        —(CR¹⁹R²⁰)_(w)—NR²⁶S(O)₂—)(CR¹⁹R²⁰)_(s)—, and        —(CR¹⁹R²⁰)_(w)—NR²⁶S(O)₂NR²⁶—(CR¹⁹R²⁰)_(s)—, preferably a bond,        —CH₂—, —CH₂C(O)—, —S(O)₂—, —S(O)₂CH₂—, —S(O)₂CH(CH₃)—,        —S(O)₂CH₂CH₂—, —S(O)₂NR³⁹—, —S(O)₂NR³⁹CH₂—, —S(O)₂NR³⁹CH(CH₃)—,        —S(O)₂NR³⁹CH₂CH₂—, —C(O)—, —C(O)CH₂—, —C(O)CH(CH₃)—,        —C(O)CH₂CH₂—, —C(O)NR³⁹—, —C(O)NR³⁹CH₂—, —C(O)NR³⁹CH(CH₃)—, and        —C(O)NR³⁹CH₂CH₂—, more preferably —C(O)NR³⁹CH₂—,        —C(O)NR³⁹CH(R⁴⁰)— or —C(O)NR³⁹CH₂CH₂—, more preferably        —C(O)NHCH₂—, —C(O)NHCH(CH₃)— or —C(O)NHCH₂CH₂—;    -   Q¹, Q¹¹, Q⁴¹, Q⁶¹, and Q¹⁴¹ are aryl or heteroaryl, wherein aryl        or heteroaryl are optionally substituted with one or more        substituents selected from the group consisting of, —OR⁴¹,        —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹,        —NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,        heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is        optionally substituted with one or more substituents selected        from the group consisting of fluoro, lower alkoxy, fluoro        substituted lower alkoxy, lower alkylthio, fluoro substituted        lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl as a substituent of Q¹,        Q¹¹, Q⁴¹, Q⁶¹, or Q¹⁴¹, or as a substituent of lower alkyl are        optionally substituted with one or more substituents selected        from the group consisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂,        —C(O)NH₂, —OR⁴², —SR⁴², —NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴²,        —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, lower alkyl, fluoro        substituted lower alkyl, and cycloalkylamino, preferably Q¹,        Q¹¹, Q⁴¹, Q⁶¹, and Q¹⁴¹ are aryl or heteroaryl, wherein aryl or        heteroaryl are optionally substituted with one or more halogen,        lower alkyl, fluoro substituted lower alkyl, —NHS(O)₂R⁴¹,        —NHC(O)R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ or —S(O)₂R⁴¹;    -   Q¹² is fluoro, chloro or —CF₃;    -   Q¹³ and Q¹⁴ are independently hydrogen, fluoro, chloro, lower        alkyl, or fluoro substituted lower alkyl;    -   Q²², Q²⁴, Q⁵² and Q⁵⁴ are independently selected from the group        consisting of hydrogen, halogen, lower alkyl, fluoro substituted        lower alkyl, —NR⁴⁴R⁴⁴ and —SR⁴⁴, provided, however, that at        least one of Q²² and Q²⁴ and at least one of Q⁵² and Q⁵⁴ is        hydrogen, fluoro, chloro, lower alkyl or fluoro substituted        lower alkyl;    -   Q⁷⁴ and Q¹⁵² are hydrogen, fluoro, chloro, lower alkyl, fluoro        substituted lower alkyl, —NR⁴⁴R⁴⁴, —OR⁴⁴, or —SR⁴⁴;    -   Q⁷² is hydrogen, lower alkyl or fluoro substituted lower alkyl;    -   R³⁹, R⁴⁰ and R⁴¹ are as defined for Formula Ig;    -   each R⁴⁴ is independently hydrogen, lower alkyl or fluoro        substituted lower alkyl; and    -   R¹⁹, R²⁰, R²¹, R²⁶, s, t and u are as defined for Formula Ib.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula IIa,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₃ is —CH₂— or —C(O)—;    -   Q^(1a) is aryl or heteroaryl, wherein aryl or heteroaryl are        optionally substituted with one or more substituents selected        from the group consisting of halogen, lower alkyl, fluoro        substituted lower alkyl, —NHR⁴¹, —NR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹;    -   Q⁵ is hydrogen, —OR⁴³, —CN, fluoro, chloro, lower alkyl, fluoro        substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or        heteroaryl are optionally substituted with one or more        substituents selected from the group consisting of halogen,        lower alkyl, fluoro substituted lower alkyl, —NHR⁴³, —NR⁴³R⁴³,        —OR⁴³ and —S(O)₂R⁴³; and    -   M₄, Q¹², Q¹³, Q¹⁴, R⁴¹, and R⁴³ are as defined for Formula II;    -   provided, however, that the compound is not

In one embodiment of compounds of Formula IIa, A₃ is —CH₂— and M₄ is—NHCH₂—. In one embodiment A₃ is —C(O)— and M₄ is —NHCH₂—. In oneembodiment A₃ is —C(O)— and M₄ is —NHC(O)—. In one embodiment A₃ is—CH₂— and M₄ is —NHC(O)—.

In one embodiment of compounds of Formula IIa, A₃ is —CH₂—, M₄ is—NHCH₂—, Q⁵ is —OR⁴³, —CN, C₁₋₃ alkyl, fluoro substituted C₁₋₃ alkyl,fluoro, chloro, aryl or heteroaryl, wherein aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴³, —NR⁴³R⁴³, —OR⁴³ and —S(O)₂R⁴³, and Q¹³ and Q¹⁴ arehydrogen.

In one embodiment of compounds of Formula IIa, A₃ is —C(O)—, M₄ is—NHCH₂, Q⁵ is —OR⁴³, —CN, C₁₋₃ alkyl, fluoro substituted C₁₋₃ alkyl,fluoro, chloro, aryl or heteroaryl, wherein aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴³, —NR⁴³R⁴³, —OR⁴³ and —S(O)₂R⁴³, and Q¹³ and Q¹⁴ arehydrogen.

In one embodiment of compounds of Formula IIa, A₃ is —C(O)—, M₄ is—NHC(O)—, Q⁵ is —OR⁴³, —CN, C₁₋₃ alkyl, fluoro substituted C₁₋₃ alkyl,fluoro, chloro, aryl or heteroaryl, wherein aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴³, —NR⁴³R⁴³, —OR⁴³ and —S(O)₂R⁴³, and Q¹³ and Q¹⁴ arehydrogen.

In one embodiment of compounds of Formula IIa, A₃ is —CH₂—, M₄ is—NHC(O)—, Q⁵ is —OR⁴³, —CN, C₁₋₃ alkyl, fluoro substituted C₁₋₃ alkyl,fluoro, chloro, aryl or heteroaryl, wherein aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴³, —NR⁴³R⁴³, —OR⁴³ and —S(O)₂R⁴³, and Q¹³ and Q¹⁴ arehydrogen.

In one embodiment of compounds of Formula IIa, A₃ is —CH₂— or —C(O)—;Q^(1a) is aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; Q⁵ is hydrogen, —CN, —OR⁴¹, fluoro, chloro,lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, whereinaryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₄ is—NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)—, —NR³⁹CH₂CH₂—, or —NR³⁹C(O)—; Q¹² is fluoro,chloro or —CF₃; and Q¹³ and Q¹⁴ are independently hydrogen, fluoro,chloro, lower alkyl, or fluoro substituted lower alkyl, wherein R⁴¹ isas defined for Formula II.

In one embodiment, further to any of the embodiments of Formula IIaabove, R⁴³ is R⁴¹ as defined for Formula Ig. In one embodiment, furtherto any of the embodiments of Formula IIa above, R⁴³ is R⁴² as definedfor Formula Ig.

In one embodiment, further to any of the embodiments of Formula IIaabove, Q^(1a) is phenyl or pyridinyl, wherein phenyl or pyridinyl aresubstituted with 1 or 2 substituents selected from the group consistingof fluoro, chloro, methyl, methoxy, trifluoromethyl, difluoromethoxy andtrifluoromethoxy; A₃ is —CH₂—; M₄ is —NHCH₂—; and Q⁵ is —CN, fluoro,chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy,trifluoromethoxy, aryl or heteroaryl, wherein aryl or heteroaryl areoptionally substituted with one or more halogen, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, or fluoro substituted loweralkoxy. In one embodiment, further to any of the embodiments of FormulaIIa above, Q^(1a) is phenyl mono substituted with chloro, preferably atthe 4-position; A₃ is —CH₂—; M₄ is —NHCH₂—; and Q⁵ is —CN, fluoro,chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy,trifluoromethoxy, aryl or heteroaryl, wherein aryl or heteroaryl areoptionally substituted with one or more halogen, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, or fluoro substituted loweralkoxy. In one embodiment, further to any of the embodiments of FormulaIIa, Q^(1a) is pyridin-3-yl monosubstituted with methyl, methoxy,trifluoromethyl, difluoromethoxy or trifluoromethoxy, preferably at the6-position; A₃ is —CH₂—; M₄ is —NHCH₂—; Q⁵ is —CN, fluoro, chloro,methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy,aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more halogen, lower alkyl, fluoro substitutedlower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.

In one embodiment of compounds of Formula IIa, A₃ is —CH₂—; M₄ is—NHCH₂—; Q^(1a) is phenyl or pyridinyl, wherein phenyl or pyridinyl aresubstituted with 1 or 2 substituents selected from the group consistingof fluoro, chloro, methyl, methoxy, trifluoromethyl, difluoromethoxy andtrifluoromethoxy; Q⁵ is hydrogen, fluoro, chloro, methyl, methoxy,trifluoromethyl, trifluoromethoxy, —CN, or 1-methyl-1H-pyrazole-4-yl;Q¹² is fluoro or chloro; and Q¹³ and Q¹⁴ are hydrogen. In oneembodiment, A₃ is —CH₂—; M₄ is —NHCH₂—; Q^(1a) is phenyl monosubstituted with chloro, preferably at the 4-position, Q⁵ is hydrogen,chloro, methyl, methoxy, or —CN; Q¹² is fluoro or chloro; and Q¹³ andQ¹⁴ are hydrogen. In one embodiment, A₃ is —C₂—; M₄ is —NHCH₂—; Q^(1a)is pyridin-3-yl monosubstituted with methyl, methoxy, trifluoromethyl,difluoromethoxy or trifluoromethoxy, preferably at the 6-position; Q⁵ ishydrogen, chloro, methyl, methoxy, —CN, or 1-methyl-1H-pyrazole-4-yl;Q¹² is fluoro or chloro; and Q¹³ and Q¹⁴ are hydrogen.

In one embodiment of compounds of Formula IIa, the compound is selectedfrom the group consisting of:

-   (4-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-amine    (P-0132),-   (4-Chloro-benzyl)-[6-chloro-5-(1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0161),-   [6-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0174),-   [6-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0176),-   {6-Chloro-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-yl}-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0179),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0186),-   [6-Fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0187),-   [6-Fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0188),-   3-{2-Chloro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0232),-   [6-Chloro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0233),-   [6-Chloro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0234),-   [6-Fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine    (P-0378),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine    (P-0379),-   (5-Fluoro-pyridin-3-ylmethyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0414),-   3-{2-Fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0415),-   3-[6-(4-Chloro-benzylamino)-2-fluoro-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0432), and    all salts, prodrugs, tautomers, and isomers thereof.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula IIb,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₂ is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S—(O)—, —S(O)₂—, —NR²¹—, and —O—;

Q¹⁵ is selected from the group consisting of hydrogen, halogen,optionally substituted lower alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, —OH, —NH₂, —NO₂, —CN, —NHC(O)NH₂—,—NHC(S)NH₂—, —NHS(O)₂NH₂—, —C(O)NH₂—, —C(S)NH₂—, —S(O)₂NH₂—, —NR²⁴R²⁵,—NHR²³, —OR²³, —SR²³, —C(O)R²³, —C(S)R²³, —S(O)R²³, —S(O)₂R²³,—C(O)NHR²³, —C(O)NR²³R²³, —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³,—S(O)₂NR²³R²³, —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³,—NHS(O)₂R²³, —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³, —NR²³C(O)NHR²³,—NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,—NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,—NR²³S(O)₂NH₂—, —NR²³S(O)₂NHR²³, —NHS and —NR²³R²³; M₅, Q¹¹, Q²² and Q²⁴are as defined for Formula II; and

-   -   R¹⁹, R²⁰, R²¹, R²³, R²⁴, and R²⁵ are as defined for Formula Ib;    -   provided, however, that the compound is not

In one embodiment of compounds of Formula IIb, M₅ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)— or—NR³⁹C(O)—, wherein R³⁹ is hydrogen or lower alkyl and R⁴⁰ is loweralkyl or fluoro substituted lower alkyl. In one embodiment, A₂ is—CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—. In one embodiment, Q¹¹is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, and —NHR²³, —NR²³R²³, —OR²³and —S(O)₂R²³ and Q¹⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, loweralkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl,aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl orheteroaryl are optionally substituted with one or more substituentsselected from the group consisting of halogen, lower alkyl, fluorosubstituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³. Furtherto any of the above embodiments, Q²² and Q²⁴ are independently hydrogen,fluoro, chloro, or —CF₃, preferably Q²² and Q²⁴ are hydrogen.

In one embodiment of compounds of Formula IIb, M₅, is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)— or—NR³⁹C(O)—, and A₂ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—.In one embodiment, M₅, is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)— or—NR³⁹C(O)—; A₂ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—; Q¹¹is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³; and Q¹⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl,fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³. In one embodiment, M₅, is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)— or—NR³⁹C(O)—; A₂ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—; Q¹¹is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³; Q¹⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl,fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; and Q²² and Q²⁴ areindependently hydrogen, fluoro, chloro, or —CF₃, preferably Q²² and Q²⁴are hydrogen.

In one embodiment of compounds of Formula IIb, M₅, is —NR³⁹CH₂—,—NR³⁹CH(R⁴⁰)—, —NR³⁹CH₂CH₂—, or —NR³⁹C(O)—; A₂ is —CH₂— or —C(O)—,preferably —CH₂—; Q¹¹ is cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹; —NR⁴¹R⁴¹; —OR⁴¹ and —S(O)₂R⁴¹; Q¹⁵ is hydrogen, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl,aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl orheteroaryl are optionally substituted with one or more substituentsselected from the group consisting of halogen, lower alkyl, fluorosubstituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and —S(O)₂R⁴¹; Q²² andQ²⁴ are independently hydrogen, fluoro, chloro, lower alkyl, or fluorosubstituted lower alkyl, preferably hydrogen, fluoro, chloro, or —CF₃,more preferably both Q²² and Q²⁴ are hydrogen, wherein R⁴¹ is as definedfor Formula Ig.

In one embodiment of compounds of Formula IIb, A₂ is —CH₂— or —C(O)—,preferably —CH₂—; Q¹¹ is cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as asubstituent of Q¹¹, or as a substituent of lower alkyl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂—, —C(O)NH₂, —OR⁴², —SR⁴²,—NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q¹⁵ ishydrogen, —CN, —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₅, is a bond, —NR³⁹—, —S—, —O—,—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, —C(O)NR³⁹—,—S(O)₂NR³⁹—, —CH₂NR³⁹—, —CH(R⁴⁰)NR³⁹—, —NR³⁹C(O)—, or —NR³⁹S(O)₂—; andQ²², and Q²⁴ are independently hydrogen, halogen, lower alkyl, fluorosubstituted lower alkyl, —NR⁴⁴R⁴⁴, —OR⁴⁴, or —SR⁴⁴, provided, however,that at least one of Q²² and Q²⁴ is hydrogen, fluoro, chloro, loweralkyl or fluoro substituted lower alkyl, wherein R³⁹, R⁴⁰, R⁴¹, and R⁴²are as defined for Formula Ig, and R⁴⁴ is as defined for Formula II.

In one embodiment of compounds of Formula IIb, A₂ is —CH₂—; Q¹¹ is arylor heteroaryl, wherein aryl or heteroaryl are optionally substitutedwith one or more substituents selected from the group consisting offluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, fluoro substituted lower alkoxy, di-alkylamino, andheterocycloalkyl; Q¹⁵ is hydrogen, —CN, fluoro, chloro, lower alkyl,fluoro substituted lower alkyl, lower alkoxy, or fluoro substitutedlower alkoxy; M₅, is —NR³⁹CH₂—, —NR³⁹CH₂CH₂—, or —NR³⁹CH(R⁴⁰)—; and Q²²and Q²⁴ are independently hydrogen, halogen, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, or fluoro substituted loweralkoxy, provided, however, that at least one of Q²² and Q²⁴ is hydrogen,fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment, further to any of the embodiments of Formula IIbabove, each occurrence of R⁴¹ is R⁴² as defined for Formula Ig.

In one embodiment of compounds of Formula IIb, M₅, is —NHCH₂CH₂—,—NHCH₂—, —N(CH₃)CH₂—, or —NHCH(CH₃)—, preferably —NHCH₂—; A₂ is —CH₂—;Q¹¹ is cycloalkyl, heterocycloalkyl, phenyl or heteroaryl, whereinphenyl or heteroaryl are optionally substituted with 1 or 2 substituentsselected from the group consisting of halogen, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,di-alkylamino, and heterocycloalkyl; Q¹⁵ is hydrogen, —CN, fluoro,chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy,fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, and fluoro substituted lower alkoxy; and Q²² andQ²⁴ are independently hydrogen, fluoro, chloro, lower alkyl, or fluorosubstituted lower alkyl, preferably hydrogen, fluoro, chloro, or —CF₃,more preferably both Q²² and Q²⁴ are hydrogen.

In one embodiment of compounds of Formula IIb, M₅, is —NHCH₂—; A₂ is—CH₂—; Q¹¹ is phenyl substituted with 1 or 2 substituents selected fromthe group consisting of fluoro, chloro, methyl, fluoro substitutedmethyl, methoxy, and fluoro substituted methoxy; Q¹⁵ is hydrogen, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, fluoro substituted lower alkoxy, preferably hydrogen or chloro;and Q²² and Q²⁴ are hydrogen.

In one embodiment of compounds of Formula IIb, the compound is selectedfrom the group consisting of:

-   (4-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0260),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,6-difluoro-benzyl)-amine    (P-0261),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0262),-   (2-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0263),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-benzyl)-amine    (P-0264),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,4-difluoro-benzyl)-amine    (P-0265),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)-amine    (P-0266),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,5-difluoro-benzyl)-amine    (P-0267),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-trifluoromethyl-benzyl)-amine    (P-0268),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-5-trifluoromethyl-benzyl)-amine    (P-0289),-   (2-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0291),-   (2,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0292),-   (2-Chloro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0293),-   (3-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0294),-   (3,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0295),-   (2-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0300),-   (2-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0301),-   [5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0302),-   [5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-benzyl)-amine    (P-0303),-   (5-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0304),-   (2,4-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0305),-   (2,4-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0306),-   (4-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0307),-   [5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)-amine    (P-0308),-   (2-Fluoro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0309),-   (2,5-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0310),-   (3-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0311),-   (2-Difluoromethoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0312),-   (2,3-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0313),-   (4-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0314),-   (5-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0315),-   (2-Chloro-4-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0316),-   (5-Chloro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0317),-   (5-Fluoro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0318),-   (2-Fluoro-4-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0319),-   (4-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0320),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-difluoromethoxy-benzyl)-amine    (P-0390),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-2-trifluoromethyl-benzyl)-amine    (P-0391),-   (3-Chloro-2-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0392),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-3-trifluoromethyl-benzyl)-amine    (P-0393),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-4-trifluoromethyl-benzyl)-amine    (P-0394),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,3-difluoro-benzyl)-amine    (P-0395),-   (2-Chloro-4-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0396),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-benzyl)-amine    (P-0402),-   (2-Chloro-5-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0407),-   (2-Chloro-5-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0408),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-4-ylmethyl-amine    (P-0416),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-pyrrolidin-1-yl-ethyl)-amine    (P-0417),-   Benzyl-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0418),-   Benzyl-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methyl-amine    (P-0419),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethoxy-benzyl)-amine    (P-0420),-   (3-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0421),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-3-ylmethyl-amine    (P-0422),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluoro-benzyl)-amine    (P-0423),-   (3-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methyl-amine    (P-0424),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3,5-difluoro-benzyl)-amine    (P-0425),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[1-(2-fluoro-phenyl)-ethyl]-amine    (P-0426),-   [1-(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0427),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[(S)-1-(4-fluoro-phenyl)-ethyl]-amine    (P-0428),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0429),-   (2-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methyl-amine    (P-0430),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methyl-benzyl)-amine    (P-0431),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-benzyl)-amine    (P-0433),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)-amine    (P-0434),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohexylmethyl-amine    (P-0435),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-2-ylmethyl-amine    (P-0436),-   [2-(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0437),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-difluoromethoxy-benzyl)-amine    (P-0438),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methoxy-benzyl)-amine    (P-0439),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-benzyl)-amine    (P-0440),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-ethyl)-amine    (P-0441),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-fluoro-benzyl)-amine    (P-0442),-   (3-Chloro-4-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0443),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-ethoxy-benzyl)-amine    (P-0444),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-morpholin-4-yl-benzyl)-amine    (P-0445),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-difluoromethoxy-benzyl)-amine    (P-0446),-   (4-Chloro-3-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0447),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[1-(3-fluoro-phenyl)-ethyl]-amine    (P-0448),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-dimethylamino-benzyl)-amine    (P-0449), and    all salts, prodrugs, tautomers, and isomers thereof.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula IIc,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₄ is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S(O)—, —S(O)₂—, —NR²¹—, and —O—;

Q²⁵ is selected from the group consisting of hydrogen, halogen,optionally substituted lower alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, —OH, —NH₂, —NO₂, —CN, —NHC(O)NH₂,—NHC(S)NH₂, —NHS(O)₂NH₂, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂—, —NR²⁴R²⁵,—NHR²³, —OR²³, —SR²³, —C(O)R²³, —C(S)R²³, —S(O)R²³, —S(O)₂R²³,—C(O)NHR²³, —C(O)NR²³R²³, —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³,—S(O)₂NR²³R²³, —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³,—NHS(O)₂R²³, —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,—NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,—NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,—NR²³S(O)₂NH₂, —NR²³S(O)₂NHR²³, —NHS(O)₂NR²³R²³, and —NR²³S(O)₂NR²³R²³;

-   -   M₆, Q²¹, Q³² and Q³³ are as defined for Formula II; and    -   R¹⁹, R²⁰, R²¹, R²³, R²⁴, and R²⁵ are as defined for Formula Ib.

In one embodiment of compounds of Formula IIc, M₆ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)— or—NR³⁹C(O)—, wherein R³⁹ is hydrogen or lower alkyl and R⁴⁰ is loweralkyl or fluoro substituted lower alkyl. In one embodiment, A₄ is—CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—. In one embodiment, Q²¹is aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ and Q²⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group NR²³R²³, —OR²³ consistingof halogen, lower alkyl, fluoro substituted lower alkyl, —NHR²³,—NR²³R²³, —OR²³ and —S(O)₂R²³. Further to any of the above embodiments,Q³² and Q³³ are independently hydrogen, fluoro, chloro, or —CF₃.

In one embodiment of compounds of Formula IIc, M₆ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)— or—NR³⁹C(O)—, and A₄ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—.In one embodiment, M₅, is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)— or—NR³⁹C(O)—; A₄ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—; Q²¹is aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; and Q²⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³. In one embodiment, M₆ is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)—or —(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably—NR²⁶—(CR¹⁹R²⁰)_(s)— or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably—NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)— or —NR³⁹C(O)—; A₄ is —CR¹⁹R²⁰— or —C(O)—,preferably —CH₂— or —C(O)—; Q²¹ is aryl or heteroaryl, wherein aryl orheteroaryl are optionally substituted with one or more substituentsselected from the group consisting of halogen, lower alkyl, fluorosubstituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; Q²⁵ ishydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluoro substitutedlower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, whereincycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; and Q³² and Q³³ are independentlyhydrogen, fluoro, chloro, or —CF₃.

In one embodiment of compounds of Formula IIc, M₆ is —NR³⁹CH₂—,—NR³⁹CH(R⁴)— or —NR³⁹C(O)—, preferably —NHCH₂—; A₄ is —CH₂— or —C(O)—,preferably —CH₂—; Q²¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and —S(O)₂R⁴¹; Q²⁵ is hydrogen, fluoro,chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy,fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and —S(O)₂R⁴¹; Q³² and Q³³ areindependently hydrogen, fluoro, chloro, lower alkyl, or fluorosubstituted lower alkyl, preferably Q³² and Q³³ are independentlyhydrogen fluoro, chloro, or —CF₃, wherein R⁴¹ is as defined for FormulaIg.

In one embodiment of compounds of Formula IIc, A₄ is —CH₂— or —C(O)—,preferably —CH₂—; Q²¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹,—NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂ ⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as asubstituent of Q²¹, or as a substituent of lower alkyl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,—NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q²⁵ ishydrogen, —CN, —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—NR³⁹C(O)R⁴¹, —NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹ fluoro, chloro, lower alkyl,fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl orheteroaryl are optionally substituted with one or more substituentsselected from the group consisting of halogen, lower alkyl, fluorosubstituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₆ is a bond,—NR³⁹—, —S—, —O—, —NR³⁹CH₂—, —NR³⁹CH₂CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—,—OCH₂—, —C(O)NR³⁹—, —S(O)₂NR³⁹—, —CH₂NR³⁹—, —CH(R⁴⁰NR³⁹—, —NR³⁹C(O)—, or—NR³⁹S(O)₂—; and Q³² and Q³³ are independently hydrogen, halogen, loweralkyl, fluoro substituted lower alkyl, —NR⁴⁴R⁴⁴, —OR⁴⁴, or —SR⁴⁴,provided, however, that at least one of Q³² and Q³³ is hydrogen, fluoro,chloro, lower alkyl or fluoro substituted lower alkyl, wherein R³⁹, R⁴⁰,R⁴¹, R⁴² and R⁴⁴ are as defined for Formula II.

In one embodiment of compounds of Formula IIc, A₄ is —CH₂—; Q²¹ is arylor heteroaryl, wherein aryl or heteroaryl are optionally substitutedwith one or more substituents selected from the group consisting offluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, and fluoro substituted lower alkoxy; Q²⁵ is hydrogen, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, or fluoro substituted lower alkoxy; M₆ is —NR³⁹CH₂—,—NR³⁹CH₂CH₂—, or —NR³⁹CH(R⁴⁰)—; and Q³² and Q³³ are independentlyhydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, or fluoro substituted lower alkoxy, provided, however, that atleast one of Q³² and Q³³ is hydrogen, fluoro, chloro, lower alkyl orfluoro substituted lower alkyl.

In one embodiment, further to any of the embodiments of Formula IIcabove, each occurrence of R⁴¹ is R⁴² as defined for Formula Ig.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula IId,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₅, is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S(O)—, —S(O)₂—, —NR²¹⁻⁵ and —O—;

Q³⁵ is selected from the group consisting of hydrogen, halogen,optionally substituted lower alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, —OH, —NH₂, —NO₂, —CN, —NHC(O)NH₂—,—NHC(S)NH₂—, —NHS(O)₂NH₂—, —C(O)NH₂—, —C(S)NH₂—, —S(O)₂NH₂—, —NR²⁴R²⁵,—NHR²³, —OR²³, —SR²³, —C(O)R²³, —C(S)R²³, —S(O)R²³, —S(O)₂R²³,—C(O)NHR²³, —C(O)NR²³R²³, —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³,S(O)₂NR²³R²³, —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³,—NHS(O)₂R²³, —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,—NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,—NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,—NR²³S(O)₂NH₂—, —NR²³S(O)₂NHR²³, —NHS and —NR

-   -   M₇, Q³¹, Q⁴³ and Q⁴⁴ are as defined for Formula II; and

R¹⁹, R²⁰, R²¹, R²³, R²⁴, and R²⁵ are as defined for Formula Ib.

In one embodiment of compounds of Formula IId, M₇ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)— or—NR³⁹C(O)—, wherein R³⁹ is hydrogen or lower alkyl and R⁴⁰ is loweralkyl or fluoro substituted lower alkyl. In one embodiment, A₅, is—CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—. In one embodiment, Q³¹is aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ and Q³⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group NR²³R²³, —OR²³ consistingof halogen, lower alkyl, fluoro substituted lower alkyl, —NHR²³,—NR²³R²³, —OR²³ and —S(O)₂R²³. Further to any of the above embodiments,Q⁴³ and Q⁴⁴ are independently hydrogen, fluoro, chloro, or —CF₃.

In one embodiment of compounds of Formula IId, M₇ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)— or—NR³⁹C(O)—, and A₅, is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—.In one embodiment, M₇ is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s), more preferably —NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)— or—NR³⁹C(O)—; A₅, is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—; Q³¹is aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; and Q³⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³. In one embodiment, M₇ is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)—or —(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably—NR²⁶—(CR¹⁹R²⁰)_(s)— or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably—NR³⁹CH₂—, —NR³⁹CH(R⁴⁰)— or —NR³⁹C(O)—; A₅, is —CR¹⁹R²⁰— or —C(O)—,preferably —CH₂— or —C(O)—; Q³¹ is aryl or heteroaryl, wherein aryl orheteroaryl are optionally substituted with one or more substituentsselected from the group consisting of halogen, lower alkyl, fluorosubstituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; Q³⁵ ishydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluoro substitutedlower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, whereincycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; and Q⁴³ and Q⁴⁴ are independentlyhydrogen, fluoro, chloro, or —CF₃.

In one embodiment of compounds of Formula IId, M₇ is —NR³⁹CH₂—,—NR³⁹CH(R⁴⁰)— or —NR³⁹C(O)—, preferably —NHCH₂—; A₅, is —CH₂— or —C(O)—,preferably —CH₂—; Q³¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and —S(O)₂R⁴¹; Q³⁵ is hydrogen, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl,aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl orheteroaryl are optionally substituted with one or more substituentsselected from the group consisting of halogen, lower alkyl, fluorosubstituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and —S(O)₂R⁴¹; Q⁴³ andQ⁴⁴ are independently hydrogen, fluoro, chloro, lower alkyl, or fluorosubstituted lower alkyl, preferably Q⁴³ and Q⁴⁴ are independentlyhydrogen, fluoro, chloro, or —CF₃, wherein R⁴¹ is as defined for FormulaIg.

In one embodiment of compounds of Formula IId, A₅, is —CH₂— or —C(O)—,preferably —CH₂—; Q³¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹,—NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as asubstituent of Q³¹, or as a substituent of lower alkyl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,—NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q³⁵ ishydrogen, —CN, —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—R³⁹C(O)R⁴¹—, —NR³⁹S(O)₂R⁴¹, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₇ is a bond, —NR³⁹—, —S—, —O—,—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, —C(O)NR³⁹—,—S(O)₂NR³⁹—, —CH₂NR³⁹—, —CH(R⁴⁰NR³⁹—, —NR³⁹C(O)—, or —NR³⁹S(O)₂—; andQ⁴³ and Q⁴⁴ are independently hydrogen, halogen, lower alkyl, fluorosubstituted lower alkyl, —NR⁴⁴R⁴⁴, —OR⁴⁴, or —SR⁴⁴, provided, however,that at least one of Q⁴³ and Q⁴⁴ is hydrogen, fluoro, chloro, loweralkyl or fluoro substituted lower alkyl, wherein R³⁹, R⁴⁰, R⁴¹, R⁴² andR⁴⁴ are as defined for Formula II.

In one embodiment of compounds of Formula IId, A₅, is —CH₂—; Q³¹ is arylor heteroaryl, wherein aryl or heteroaryl are optionally substitutedwith one or more substituents selected from the group consisting offluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, and fluoro substituted lower alkoxy; Q³⁵ is hydrogen, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, or fluoro substituted lower alkoxy; M₇ is —NR³⁹CH₂—,—NR³⁹CH₂CH₂—, or —NR³⁹CH(R⁴⁰)—; and Q⁴³ and Q⁴⁴ are independentlyhydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, or fluoro substituted lower alkoxy, provided, however, that atleast one of Q⁴³ and Q⁴⁴ is hydrogen, fluoro, chloro, lower alkyl orfluoro substituted lower alkyl.

In one embodiment, further to any of the embodiments of Formula IIdabove, each occurrence of R⁴¹ is R⁴² as defined for Formula Ig.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula He,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₆ is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S(O)—, —S(O)₂—, —NR²¹—, and —O—;

Q⁴⁵ is selected from the group consisting of hydrogen, halogen,optionally substituted lower alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, —OH, —NH₂, —NO₂, —CN, —NHC(O)NH₂—,—NHC(S)NH₂—, —NHS(O)₂NH₂—, —C(O)NH₂—, —C(S)NH₂—, —S(O)₂NH₂—, —NR²⁴R²⁵,—NHR²³, —OR²³, —SR²³, —C(O)R²³, —C(S)R²³, —S(O)R²³, —S(O)₂R²³,—C(O)NHR²³, —C(O)NR²³R²³, —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³,—S(O)₂NR²³R²³, —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³,—NHS(O)₂R²³, —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,—NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,—NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,—NR²³S(O)₂NH₂—, —NR²³S(O)₂NHR²³, —NHS(O)₂NR²³R²³, and —NR²³S(O)₂NR²³R²³;

-   -   M₈, Q⁴¹, Q⁵² and Q⁵⁴ are as defined in Formula II; and    -   R¹⁹, R²⁰, R²¹, R²³, R²⁴, and R²⁵ are as defined for Formula Ib;        provided, however, that the compound is not

In one embodiment of compounds of Formula IIe, M₈ is—(CR¹⁹R²⁰)_(t)—C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—, preferably—C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—, more preferably —C(O)NR³⁹—CR⁸⁰R⁸⁰— or—C(O)NR³⁹—(CR⁸⁰R⁸⁰)₂—, wherein R³⁹ is hydrogen or lower alkyl and R⁸⁰ ishydrogen, lower alkyl or fluoro substituted lower alkyl, preferablyhydrogen. In one embodiment, A₆ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂—or —C(O)—. In one embodiment, Q⁴¹ is aryl or heteroaryl, wherein aryl orheteroaryl are optionally substituted with one or more substituentsselected from the group consisting of halogen, lower alkyl, fluorosubstituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ and Q⁴⁵is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluoro substitutedlower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, whereincycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³. Further to any of the aboveembodiments, Q⁵² and Q⁵⁴ are independently hydrogen, fluoro, chloro,methyl, or —CF₃.

In one embodiment of compounds of Formula IIe, M₈ is—(CR¹⁹R²⁰)_(t)—C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—, preferably—C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—, more preferably —C(O)NR³⁹—CR⁸⁰R⁸⁰— or—C(O)NR³⁹—(CR⁸⁰R⁸⁰)₂—, and A₆ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂—or —C(O)—. In one embodiment, M₈ is—(CR¹⁹R²⁰)_(t)—C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—, preferably—C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—, more preferably —C(O)NR³⁹—CR⁸⁰R⁸⁰— or—C(O)NR³⁹—(CR⁸⁰R⁸⁰)₂—; A₆ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—; Q⁴¹ is aryl or heteroaryl, wherein aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; and Q⁴⁵ is hydrogen,—OR²³, —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³. In one embodiment, M₈ is—(CR¹⁹R²⁰)_(t)—C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—, preferably—C(O)NR²⁶—(CR¹⁹R²⁰)_(s)—, more preferably —C(O)NR³⁹—CR⁸⁰R⁸⁰— or—C(O)NR³⁹—(CR⁸⁰R⁸⁰)₂—; A₆ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—; Q⁴¹ is aryl or heteroaryl, wherein aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; Q⁴⁵ is hydrogen, —OR²³,—CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³; and Q⁵² and Q⁵⁴ are independently hydrogen, fluoro, chloro,methyl, or —CF₃.

In one embodiment of compounds of Formula IIe, M₈ is —C(O)NR³⁹—CH₂—,—C(O)NR³⁹CH(CH₃)—, or —C(O)NR³⁹—(CH₂)₂—; A₆ is —CH₂— or —C(O)—,preferably —CH₂—; Q⁴¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and —S(O)₂R⁴¹; Q⁴⁵ is hydrogen, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl,aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl orheteroaryl are optionally substituted with one or more substituentsselected from the group consisting of halogen, lower alkyl, fluorosubstituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and —S(O)₂R⁴¹; and Q⁵²and Q⁵⁴ are independently hydrogen, fluoro, chloro, lower alkyl, orfluoro substituted lower alkyl, preferably Q⁵² and Q⁵⁴ are independentlyfluoro, chloro, methyl, or —CF₃, wherein R⁴¹ is as defined in FormulaIg.

In one embodiment of compounds of Formula IIe, A₆ is —CH₂— or —C(O)—,preferably —CH₂—; Q⁴¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹,—NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as asubstituent of Q⁴¹, or as a substituent of lower alkyl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,—NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q⁴⁵ ishydrogen, —CN, —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₈ is —C(O)NR³⁹CH₂—,—C(O)NR³⁹CH(R⁴⁰)—, or —C(O)NR³⁹CH₂CH₂—; and Q⁵² and Q⁵⁴ areindependently hydrogen, halogen, lower alkyl, fluoro substituted loweralkyl, —NR⁴⁴R⁴⁴, —OR⁴⁴, or —SR⁴⁴, provided, however, that at least oneof Q⁵² and Q⁵⁴ is hydrogen, fluoro, chloro, lower alkyl or fluorosubstituted lower alkyl, wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴⁴ are asdefined for Formula II.

In one embodiment of compounds of Formula IIe, A₆ is —CH₂—; Q⁴¹ is arylor heteroaryl, wherein aryl or heteroaryl are optionally substitutedwith one or more substituents selected from the group consisting offluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, and fluoro substituted lower alkoxy; Q⁴⁵ is hydrogen, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, or fluoro substituted lower alkoxy; M₈ is —C(O)NR³⁹CH₂—,—C(O)NR³⁹CH(R⁴⁰)—, or —C(O)NR³⁹CH₂CH₂—; and Q⁵² and Q⁵⁴ areindependently hydrogen, halogen, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided,however, that at least one of Q⁵² and Q⁵⁴ is hydrogen, fluoro, chloro,lower alkyl or fluoro substituted lower alkyl.

In one embodiment, further to any of the embodiments of Formula Heabove, each occurrence of R⁴¹ is R⁴² as defined for Formula Ig.

In one embodiment of compounds of Formula He, Mg is —C(O)NHCH₂—,—C(O)NH—CH(CH₃)— or —C(O)NH—(CH₂)₂—; A₆ is —CH₂— or —C(O)—, preferably—CH₂—; Q⁴¹ is aryl or heteroaryl, wherein aryl or heteroaryl areoptionally substituted with 1 or 2 substituents selected from the groupconsisting of fluoro, chloro, methyl, fluoro substituted methyl,methoxy, and fluoro substituted methoxy; Q⁴⁵ is hydrogen, —CN, fluoro,chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, orfluoro substituted lower alkoxy, preferably hydrogen or chloro; and Q⁵²and Q⁵⁴ are independently hydrogen, fluoro, chloro, lower alkyl, orfluoro substituted lower alkyl, preferably Q⁵² and Q⁵⁴ are methyl.

In one embodiment of compounds of Formula He, the compound is selectedfrom the group consisting of:

-   3-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine    (P-0133),-   2-[3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazol-1-yl]-1-phenyl-ethanone    (P-0134),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 4-methoxy-benzylamide (P-0135),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 2-chloro-benzylamide (P-0136),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 2-fluoro-benzylamide (P-0137),-   3-[3,5-Dimethyl-1-(5-trifluoromethyl-furan-2-ylmethyl)-1H-pyrazol-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine    (P-0138),-   3-[3,5-Dimethyl-1-(5-methyl-isoxazol-3-ylmethyl)-1H-pyrazol-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine    (P-0139),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 4-chloro-benzylamide (P-0140),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid [2-(4-methoxy-phenyl)-ethyl]-amide (P-0141),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 3-methoxy-benzylamide (P-0142),-   3-{3,5-Dimethyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrazol-4-ylmethyl}-1H-pyrrolo[2,3-b]pyridine    (P-0143),-   3-[3,5-Dimethyl-1-(4-methyl-2-phenyl-thiazol-5-ylmethyl)-1H-pyrazol-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine    (P-0144),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 2-methoxy-benzylamide (P-0145),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid [2-(2,4-dichloro-phenyl)-ethyl]-amide (P-0146),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid [2-(4-fluoro-phenyl)-ethyl]-amide (P-0147),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid [2-(2-fluoro-phenyl)-ethyl]-amide (P-0148),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid ((S)-1-phenyl-ethyl)-amide (P-0149),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 3-fluoro-benzylamide (P-0150),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 4-fluoro-benzylamide (P-0151),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 4-methyl-benzylamide (P-0152),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 2-methyl-benzylamide (P-0153),-   4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic    acid [2-(4-fluoro-phenyl)-ethyl]-amide (P-0157),-   4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic    acid 4-fluoro-benzylamide (P-0158),-   4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic    acid 4-chloro-benzylamide (P-0159),-   4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic    acid-   [(S)-1-(4-fluoro-phenyl)-ethyl]-amide (P-0160), and    all salts, prodrugs, tautomers, and isomers thereof.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula IIf,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₇, is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S(O)—, —S(O)₂—, —NR²¹—, and —O—;    -   Q⁵⁵ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —NH₂,        —NO₂, —CN, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(O)NH₂,        —C(S)NH₂, —S(O)₂NH₂—, —NR²⁴R²⁵, —NHR²³, —OR²³, —SR²³, —C(O)R²³,        —C(S)R²³, —S(O)R²³, —S(O)₂R²³, —C(O)NHR²³, —C(O)NR²³R²³,        —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³, —S(O)₂NR²³R²³,        —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³, —NHS(O)₂R²³,        —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,        —NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,        —NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂HR²³,        —NR²³S(O)₂NH₂, —NR²³S(O)₂NHR²³, —NHS and —NR    -   M₉, Q⁵¹, Q⁶², and Q⁶⁴ are as defined for Formula II; and    -   R¹⁹, R²⁰, R²¹, R²³, R²⁴, and R²⁵ are as defined for Formula Ib.

In one embodiment of compounds of Formula IIf, M₉ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰) wherein R³⁹ is hydrogen or lower alkyl and R⁸⁰ ishydrogen, lower alkyl or fluoro substituted lower alkyl, preferablyhydrogen. In one embodiment, A₇ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂—or —C(O)—. In one embodiment, Q⁵¹ is optionally substituted lower alkyl,aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ and Q⁵⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³. Further to any of the above embodiments, Q⁶² is hydrogen,fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment of compounds of Formula IIf, M₉ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—, and A₇ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—. In one embodiment, M₉ is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—; A₇ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—;Q⁵¹ is optionally substituted lower alkyl, aryl or heteroaryl, whereinaryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³;and Q⁵⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³.

In one embodiment, M₉ is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰—,—NR³⁹(CR⁸⁰R⁸⁰)₂—; A₇ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—;Q⁵¹ is optionally substituted lower alkyl, aryl or heteroaryl, whereinaryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group NR²³R²³, —OR²³ consisting ofhalogen, lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³,—OR²³ and —S(O)₂R²³; Q⁵⁵ is hydrogen, —CN, fluoro, chloro, lower alkyl,fluoro substituted lower alkyl, lower alkoxy, fluoro substituted loweralkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein arylor heteroaryl are optionally substituted with one or more substituentsselected from the group consisting of halogen, lower alkyl, fluorosubstituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; and Q⁶²is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted loweralkyl.

In one embodiment of compounds of Formula IIf, M₉ is —NR³⁹CH₂— or—NR³⁹—(CH₂)₂—; A₇ is —CH₂— or —C(O)—, preferably —CH₂—; Q⁵¹ is aryl orheteroaryl, wherein aryl or heteroaryl are optionally substituted withone or more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹; —OR⁴¹ and—S(O)₂R⁴¹; Q⁵⁵ is hydrogen, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein aryl orheteroaryl are optionally substituted with one or more substituentsselected from the group consisting of halogen, lower alkyl, fluorosubstituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and —S(O)₂R⁴¹; and Q⁶²is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted loweralkyl, wherein R⁴¹ is as defined in Formula Ig.

In one embodiment of compounds of Formula IIf, A₇ is —CH₂— or —C(O)—,preferably —CH₂—; Q⁵¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹,—NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as asubstituent of Q⁵¹, or as a substituent of lower alkyl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,—NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q⁵⁵ ishydrogen, —CN, —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹ fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₉ is a bond, —NR³⁹—, —S—, —O—,—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, —C(O)NR³⁹—,—S(O)₂NR³⁹—, —CH₂NR³⁹—, —CH(R⁴⁰)NR³⁹—NR³⁹C(O)—, or —NR³⁹S(O)₂—; Q⁶² ishydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,—NR⁴⁴R⁴⁴, —OR⁴⁴, or —SR⁴⁴; and Q⁶⁴ is hydrogen, lower alkyl, or fluorosubstituted lower alkyl, wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴⁴ are asdefined for Formula II.

In one embodiment of compounds of Formula IIf, A₇ is —CH₂—; Q⁵¹ is arylor heteroaryl, wherein aryl or heteroaryl are optionally substitutedwith one or more substituents selected from the group consisting offluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, and fluoro substituted lower alkoxy; Q⁵⁵ is hydrogen, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, or fluoro substituted lower alkoxy; M₉ is —NR³⁹CH₂—,—NR³⁹CH₂CH₂—, or —NR³⁹CH(R⁴⁰)—; Q⁶² is hydrogen, fluoro, chloro, loweralkyl, fluoro substituted lower alkyl, lower alkoxy, or fluorosubstituted lower alkoxy; and Q⁶⁴ is hydrogen, lower alkyl, or fluorosubstituted lower alkyl.

In one embodiment, further to any of the embodiments of Formula IIfabove, each occurrence of R⁴¹ is R⁴² as defined for Formula Ig.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula IIg,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₈ is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S(O)—, —S(O)₂—, —NR²¹—, and —O—;    -   Q⁶⁵ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —NH₂,        —NO₂, —CN, —NHC(O)NH₂—, —NHC(S)NH₂—, —NHS(O)₂NH₂—, —C(O)NH₂—,        —C(S)NH₂—, —S(O)₂NH₂—, —NR²⁴R²⁵, —NHR²³, —OR²³, —SR²³, —C(O)R²³,        —C(S)R²³, —S(O)R²³, —S(O)₂R²³, —C(O)NHR²³, —C(O)NR²³R²³,        —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³, —S(O)₂NR²³R²³,        —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³, —NHS(O)₂R²³,        —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,        —NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,        —NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,        —NR²³S(O)₂NH₂—, —NR²³S(O)₂NHR²³, —NHS(O)₂NR²³R²³, and        —NR²³S(O)₂NR²³R²³;    -   M₁₀, Q⁶¹, Q⁷², Q⁷⁴ are as defined for Formula II; and    -   R¹⁹, R²⁰, R²¹, R²³, R²⁴, and R²⁵R²⁶ are as defined for Formula        Ib.

In one embodiment of compounds of Formula IIg, M₁₀ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹CR⁸⁰R⁸⁰)₂—, wherein R³⁹ is hydrogen or lower alkyl and R⁸⁰ ishydrogen, lower alkyl or fluoro substituted lower alkyl, preferablyhydrogen. In one embodiment, A₈ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂—or —C(O)—. In one embodiment, Q⁶¹ is optionally substituted lower alkyl,aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ and Q⁶⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³. Further to any of the above embodiments, Q⁷⁴ is hydrogen,fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment of compounds of Formula IIg, M₁₀ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or —(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR)_(s)—,preferably —NR²⁶—(CR¹⁹R²⁰)_(s)— or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, morepreferably —NR³⁹CR⁸⁰R⁸⁰— or —NR³⁹(CR⁸⁰R⁸⁰)₂—, and A₈ is —CR¹⁹R²⁰— or—C(O)—, preferably —CH₂— or —C(O)—. In one embodiment, M₁₀ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)—, or—(CR¹⁹R²⁰)_(t)—N²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—; A₈ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—;Q⁶¹ is optionally substituted lower alkyl, aryl or heteroaryl, whereinaryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³;and Q⁶⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³. In one embodiment, M₁₀ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—; A₈ is —CR¹⁹R²⁰— or —C(O)—, preferably CH₂— or —C(O)—;Q⁶¹ is optionally substituted lower alkyl, aryl or heteroaryl, whereinaryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³;Q⁶⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; and Q⁷⁴ is hydrogen,fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment of compounds of Formula IIg, M₁₀ is —NR³⁹CH₂— or—NR³⁹—(CH₂)₂—; A₈ is —CH₂— or —C(O)—, preferably —CH₂—; Q⁶¹ is aryl orheteroaryl, wherein aryl or heteroaryl are optionally substituted withone or more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and—S(O)₂R⁴¹; Q⁶⁵ is hydrogen, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and—S(O)₂R⁴¹; and Q⁷⁴ is hydrogen, fluoro, chloro, lower alkyl or fluorosubstituted lower alkyl, wherein R⁴¹ is as defined for Formula Ig.

In one embodiment of compounds of Formula IIg, A₈ is —CH₂— or —C(O)—,preferably —CH₂—; Q⁶¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹,—NR⁴¹R⁴¹, NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as asubstituent of Q⁶¹, or as a substituent of lower alkyl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,—NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q⁶⁵ ishydrogen, —CN, —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₁₀ is a bond, —NR³⁹—, —S—, —O—,—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, —C(O)NR³⁹—,—S(O)₂NR³⁹—, —CH₂NR³⁹—, —CH(R⁴⁰NR³⁹—, —NR³⁹C(O)—, or —NR³⁹S(O)₂—; Q⁷⁴ ishydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,—NR⁴⁴R⁴⁴, —OR⁴⁴, or —SR⁴⁴; and Q⁷² is hydrogen, lower alkyl, or fluorosubstituted lower alkyl, wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴⁴ are asdefined for Formula II.

In one embodiment of compounds of Formula IIg, A₈ is —CH₂—; Q⁶¹ is arylor heteroaryl, wherein aryl or heteroaryl are optionally substitutedwith one or more substituents selected from the group consisting offluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, and fluoro substituted lower alkoxy; Q⁶⁵ is hydrogen, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, or fluoro substituted lower alkoxy; M₁₀ is —NR³⁹CH₂—,—NR³⁹CH₂CH₂—, or —NR³⁹CH(R⁴⁰)—; Q⁷⁴ is hydrogen, fluoro, chloro, loweralkyl, fluoro substituted lower alkyl, lower alkoxy, or fluorosubstituted lower alkoxy; and Q⁷² is hydrogen, lower alkyl, or fluorosubstituted lower alkyl.

In one embodiment, further to any of the embodiments of Formula IIgabove, each occurrence of R⁴¹ is R⁴² as defined for Formula Ig.

In one embodiment of compounds of Formula IIg, M₁₀ is —NHCH₂—, A₈ is—CH₂—, Q⁶¹ is phenyl optionally substituted with 1 or 2 substituentsselected from the group consisting of fluoro, chloro, methyl,trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy, Q⁶⁵ ishydrogen, fluoro, —CN, or 1-methyl-pyrazol-4-yl, Q⁷² is lower alkyl orfluoro substituted lower alkyl, and Q⁷⁴ is hydrogen, fluoro, chloro,lower alkyl, or fluoro substituted lower alkyl. In one embodiment, M₁₀is —NHCH₂—, A₈ is —CH₂—, Q⁶¹ is 4-fluoro-phenyl, Q⁶⁵ is hydrogen,chloro, —CN, or 1-methyl-pyrazol-4-yl, Q⁷² is methyl or ethyl and Q⁷⁴ ishydrogen or chloro.

In one embodiment, the compound of Formula IIg is selected from thegroup consisting of:

-   [1-Ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine    (P-0165),-   (4-Fluoro-benzyl)-[1-methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-amine    (P-0169),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine    (P-0170),-   (4-Fluoro-benzyl)-{1-methyl-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-1H-pyrazol-3-yl}-amine    (P-0180),-   (5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]-methanone    (P-0184),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-ethyl-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine    (P-0185),-   3-[5-(4-Fluoro-benzylamino)-2-methyl-2H-pyrazol-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0191),-   (3-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-amine    (P-0410),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-(2,5-difluoro-benzyl)-amine    (P-0411),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-(2-fluoro-benzyl)-amine    (P-0413), and    all salts, prodrugs, tautomers, and isomers thereof.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula IIh,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₉ is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S(O)—, —S(O)₂—, —NR²¹—, and —O—;    -   Q⁷⁵ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —NH₂,        —NO₂, —CN, —NHC(O)NH₂—, —NHC(S)NH₂—, —NHS(O)₂NH₂—, —C(O)NH₂,        —C(S)NH₂—, —S(O)₂NH₂—, —NR²⁴R²⁵, —NHR²³, —OR²³, —SR²³, —C(O)R²³,        —C(S)R²³, —S(O)R²³, —S(O)₂R²³, —C(O)NHR²³, —C(O)NR²³R²³,        —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³, —S(O)₂NR²³R²³,        —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³, —NHS(O)₂R²³,        —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,        —NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,        —NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,        —NR²³S(O)₂NH₂—, —NR²³S(O)₂NHR²³, —NHS(O)₂NR²³R²³, and —NR    -   M₁₁, Q⁷¹, and Q⁸² are as defined for Formula II; and    -   R¹⁹, R²⁰, R²¹, R²³, R²⁴, and R²⁵ are as defined for Formula Ib.

In one embodiment of compounds of Formula IIh, M₁₁ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰) wherein R³⁹ is hydrogen or lower alkyl and R⁸⁰ ishydrogen, lower alkyl or fluoro substituted lower alkyl, preferablyhydrogen. In one embodiment, A₉ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂—or —C(O)—. In one embodiment, Q⁷¹ is optionally substituted lower alkyl,aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ and Q⁷⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³.

In one embodiment of compounds of Formula IIh, M₁₁ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰,)₂—, and A₉ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—. In one embodiment, M₁₁ is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—; A₉ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—;Q⁷¹ is optionally substituted lower alkyl, aryl or heteroaryl, whereinaryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³;and Q⁷⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³.

In one embodiment of compounds of Formula IIh, M₁₁ is —NR³⁹CH₂— or—NR³⁹—(CH₂)₂—; A₉ is —CH₂— or —C(O)—, preferably —CH₂—; Q⁷¹ is aryl orheteroaryl, wherein aryl or heteroaryl are optionally substituted withone or more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and—S(O)₂R⁴¹; Q⁷⁵ is hydrogen, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and—S(O)₂R⁴¹, wherein R⁴¹ is as defined for Formula Ig.

In one embodiment of compounds of Formula IIh, A₉ is —CH₂— or —C(O)—,preferably —CH₂—; Q⁷¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹,—NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as asubstituent of Q⁷¹, or as a substituent of lower alkyl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,—NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q⁷⁵ ishydrogen, —CN, —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₁₁ is a bond, —NR³⁹—, —S—, —O—,—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, —C(O)NR³⁹—,—S(O)₂NR³⁹—, —CH₂NR³⁹—, —CH(R⁴⁰NR³⁹—, —NR³⁹C(O)—, or —NR³⁹S(O)₂—; andQ⁸² is hydrogen, lower alkyl, or fluoro substituted lower alkyl, whereinR³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴⁴ are as defined for Formula II.

In one embodiment of compounds of Formula IIh, A₉ is —CH₂—; Q⁷¹ is arylor heteroaryl, wherein aryl or heteroaryl are optionally substitutedwith one or more substituents selected from the group consisting offluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, and fluoro substituted lower alkoxy; Q⁷⁵ is hydrogen, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, or fluoro substituted lower alkoxy; M₁₁ is —NR³⁹CH₂—,—NR³⁹CH₂CH₂—, or —NR³⁹CH(R⁴⁰)—; and Q⁸² is hydrogen, lower alkyl, orfluoro substituted lower alkyl.

In one embodiment, further to any of the embodiments of Formula IIhabove, each occurrence of R⁴¹ is R⁴² as defined for Formula Ig.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula III,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₁₀ is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S(O)—, —S(O)₂—, —NR²¹—, and —O—;    -   Q⁸⁵ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —NH₂,        —NO₂, —CN, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(O)NH₂,        —C(S)NH₂, —S(O)₂NH₂, —NR²⁴R²⁵, —NHR²³, —OR²³, —SR²³, —C(O)R²³,        —C(S)R²³, —S(O)R²³, —S(O)₂R²³, —C(O)NHR²³, —C(O)NR²³R²³,        —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³, —S(O)₂NR²³R²³,        —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³, —NHS(O)₂R²³,        —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,        —NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,        —NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,        —NR²³S(O)₂NH₂, —NR²³S(O)₂NHR²³, —NHS(O)₂NR²³R²³, and —NR    -   M₁₂, Q⁸¹, and Q⁹⁴ are as defined for Formula II; and    -   R¹⁹, R²⁰, R²¹, R²³, R²⁴, and R²⁵ are as defined for Formula Ib.

In one embodiment of compounds of Formula III, M₁₂ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰) wherein R³⁹ is hydrogen or lower alkyl and R⁸⁰ ishydrogen, lower alkyl or fluoro substituted lower alkyl, preferablyhydrogen. In one embodiment, A₁₀ is —CR¹⁹R²⁰— or —C(O)—, preferably—CH₂— or —C(O)—. In one embodiment, Q⁸¹ is optionally substituted loweralkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ and Q⁸⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³.

In one embodiment of compounds of Formula III, M₁₂ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—, and A₁₀ is —CR¹⁹R²⁰)_(s)— or —C(O)—, preferably —CH₂—or —C(O)—. In one embodiment, M₁₂ is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)—or —(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably) or—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)— or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably—NR³⁹CR⁸⁰R⁸⁰— or —NR³⁹(CR⁸⁰R⁸⁰)₂—, and A₁₀ is —CR¹⁹R²⁰— or —C(O)—,preferably —CH₂— or —C(O)—; Q⁸¹ is optionally substituted lower alkyl,aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; and Q⁸⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³.

In one embodiment of compounds of Formula III, M₁₂ is —NR³⁹CH₂— or—NR³⁹—(CH₂)₂—; A₁₀ is —CH₂— or —C(O)—, preferably —CH₂—; Q⁸¹ is aryl orheteroaryl, wherein aryl or heteroaryl are optionally substituted withone or more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and—S(O)₂R⁴¹; Q⁸⁵ is hydrogen, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and—S(O)₂R⁴¹, wherein R⁴¹ is as defined for Formula Ig.

In one embodiment of compounds of Formula III, A₁₀ is —CH₂— or —C(O)—,preferably —CH₂—; Q⁸¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹,—NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as asubstituent of Q⁸¹, or as a substituent of lower alkyl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,—NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q⁸⁵ ishydrogen, —CN, —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₁₂ is a bond, —NR³⁹—, —S—, —O—,—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, —C(O)NR³⁹—,—S(O)₂NR³⁹—, —CH₂NR³⁹—, —CH(R⁴⁰NR³⁹—, —NR³⁹C(O)—, or —NR³⁹S(O)₂—; andQ⁹⁴ is hydrogen, lower alkyl, or fluoro substituted lower alkyl, whereinR³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴⁴ are as defined for Formula II.

In one embodiment of compounds of Formula III, A₁₀ is —CH₂—; Q⁸¹ is arylor heteroaryl, wherein aryl or heteroaryl are optionally substitutedwith one or more substituents selected from the group consisting offluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, and fluoro substituted lower alkoxy; Q⁸⁵ is hydrogen, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, or fluoro substituted lower alkoxy; M₁₂ is —NR³⁹CH₂—,—NR³⁹CH₂CH₂—, or —NR³⁹CH(R⁴⁰)—; and Q⁹⁴ is hydrogen, lower alkyl, orfluoro substituted lower alkyl.

In one embodiment, further to any of the embodiments of Formula IIIabove, each occurrence of R⁴¹ is R⁴² as defined for Formula Ig.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula IIj,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₁₁ is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S(O)—, and —S(O)₂—;    -   Q⁹⁵ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —NH₂,        —NO₂, —CN, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(O)NH₂,        —C(S)NH₂, —S(O)₂NH₂, —NR²⁴R²⁵, —NHR²³, —OR²³, —SR²³, —C(O)R²³,        —C(S)R²³, —S(O)R²³, —S(O)₂R²³, —C(O)NHR²³, —C(O)NR²³R²³,        —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³, —S(O)₂NR²³R²³,        —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³, —NHS(O)₂R²³,        —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,        —NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,        —NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,        —NR²³S(O)₂NH₂—, —NR²³S(O)₂NHR²³, —NHS(O)₂NR²³R²³, and —NR    -   M₁₃, Q⁹¹, Q¹⁰² and Q¹⁰⁴ are as defined for Formula II; and    -   R¹⁹, R²⁰, R²³, R²⁴, and R²⁵ are as defined for Formula Ib.

In one embodiment of compounds of Formula IIj, M₁₃ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—, wherein R³⁹ is hydrogen or lower alkyl and R⁸⁰ ishydrogen, lower alkyl or fluoro substituted lower alkyl, preferablyhydrogen. In one embodiment, A₁₁ is —CR¹⁹R²⁰— or —C(O)—, preferably—CH₂— or —C(O)—. In one embodiment, Q⁹¹ is optionally substituted loweralkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ and Q⁹⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³. Further to any of the above embodiments, Q¹⁰² and Q¹⁰⁴ areindependently hydrogen, fluoro, chloro, methyl, or —CF₃.

In one embodiment of compounds of Formula IIj, M₁₃ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—, and A₁₁ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—. In one embodiment, M₁₃ is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—; A₁₁ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—; Q⁹¹ is optionally substituted lower alkyl, aryl or heteroaryl,wherein aryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³;and Q⁹⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³. In one embodiment, M₁₃ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—,more preferably —NR³⁹CR⁸⁰R⁸⁰— or —NR³⁹(CR⁸⁰R⁸⁰)₂—; A₁₁ is —CR¹⁹R²⁰— or—C(O)—, preferably —CH₂— or —C(O)—; Q⁹¹ is optionally substituted loweralkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupNR²³R²³, —OR²³ consisting of halogen, lower alkyl, fluoro substitutedlower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; Q⁹⁵ is hydrogen,—OR²³, —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³; and Q¹⁰² and Q¹⁰⁴ are independently hydrogen, fluoro, chloro,methyl, or —CF₃.

In one embodiment of compounds of Formula IIj, M₁₃ is —NR³⁹CH₂— or—NR³⁹—(CH₂)₂—; A₁₁ is —CH₂— or —C(O)—, preferably —CH₂—; Q⁹¹ is aryl orheteroaryl, wherein aryl or heteroaryl are optionally substituted withone or more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —N⁴¹R⁴¹, —OR⁴¹ and—S(O)₂R⁴¹; Q⁹⁵ is hydrogen, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹, —OR⁴¹ and—S(O)₂R⁴¹; and Q¹⁰² and Q¹⁰⁴ are independently hydrogen, fluoro, chloro,lower alkyl, or fluoro substituted lower alkyl, preferably Q¹⁰² and Q¹⁰⁴are independently hydrogen, fluoro, chloro, methyl, or —CF₃, wherein R⁴¹is as defined for Formula Ig.

In one embodiment of compounds of Formula IIj, A₁₁ is —CH₂— or —C(O)—,preferably —CH₂—; Q⁹¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹,—NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as asubstituent of Q⁹¹, or as a substituent of lower alkyl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,—NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q⁹⁵ ishydrogen, —CN, —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₁₃ is a bond, —NR³⁹—, —S—, —O—,—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, —C(O)NR³⁹—,—S(O)₂NR³⁹—, —CH₂NR³⁹—, —CH(R⁴⁰NR³⁹—, —NR³⁹C(O)—, or —NR³⁹S(O)₂—; andQ¹⁰² and Q¹⁰⁴ are independently hydrogen, halogen, lower alkyl, fluorosubstituted lower alkyl, —NR⁴⁴R⁴⁴, —OR⁴⁴, or —SR⁴⁴, provided, however,that at least one of Q¹⁰² and Q¹⁰⁴ is hydrogen, fluoro, chloro, loweralkyl or fluoro substituted lower alkyl, wherein R³⁹, R⁴⁰, R⁴¹, R⁴² andR⁴⁴ are as defined for Formula II.

In one embodiment of compounds of Formula IIj, A₁₁ is —CH₂—; Q⁹¹ is arylor heteroaryl, wherein aryl or heteroaryl are optionally substitutedwith one or more substituents selected from the group consisting offluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, and fluoro substituted lower alkoxy; Q⁹⁵ is hydrogen, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, or fluoro substituted lower alkoxy; M₁₃ is —NR³⁹CH₂—,—NR³⁹CH₂CH₂—, or —NR³⁹CH(R⁴⁰)—; and Q¹⁰² and Q¹⁰⁴ are independentlyhydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, or fluoro substituted lower alkoxy, provided, however, that atleast one of Q¹⁰² and Q¹⁰⁴ is hydrogen, fluoro, chloro, lower alkyl orfluoro substituted lower alkyl.

In one embodiment, further to any of the embodiments of Formula IIjabove, each occurrence of R⁴¹ is R⁴² as defined for Formula Ig.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula IIk,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₁₂ is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S(O)—, and —S(O)₂—;    -   Q¹⁰⁵ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —NH₂,        —NO₂, —CN, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(O)NH₂,        —C(S)NH₂, —S(O)₂NH₂—, —NR²⁴R²⁵, —NHR²³, —OR²³, —SR²³, —C(O)R²³,        —C(S)R²³, —S(O)R²³, —S(O)₂R²³, —C(O)NHR²³, —C(O)NR²³R²³,        —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³, —S(O)₂NR²³R²³,        —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³, —NHS(O)₂R²³,        —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,        —NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,        —NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,        —NR²³S(O)₂NH₂, —NR²³S(O)₂NHR²³, —NHS(O)₂NR²³R²³, and —NR²³R²³;    -   M₁₄, Q¹⁰¹, and Q¹¹² are as defined for Formula II; and    -   R¹⁹, R²⁰, R²³, R²⁴, and R²⁵ are as defined for Formula Ib.

In one embodiment of compounds of Formula IIk, M₁₄ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—,or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰) wherein R³⁹ is hydrogen or lower alkyl and R⁸⁰ ishydrogen, lower alkyl or fluoro substituted lower alkyl, preferablyhydrogen. In one embodiment, A₁₂ is —CR¹⁹R²⁰— or —C(O)—, preferably—CH₂— or —C(O)—. In one embodiment, Q¹⁰¹ is optionally substituted loweralkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ and Q¹⁰⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³. Further to any of the above embodiments, Q¹¹² is hydrogen,fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment of compounds of Formula IIk, M₁₄ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—, and A₁₂ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—. In one embodiment, M₁₄ is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—; A₁₂ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—; Q¹⁰¹ is optionally substituted lower alkyl, aryl or heteroaryl,wherein aryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³;and Q¹⁰⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³. In one embodiment, M₁₄ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—; A₁₂ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—; Q¹⁰¹ is optionally substituted lower alkyl, aryl or heteroaryl,wherein aryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³;Q¹⁰⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; and Q¹¹² is hydrogen,fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment of compounds of Formula IIk, M₁₄ is —NR³⁹CH₂— or—NR³⁹—(CH₂)₂—; A₁₂ is —CH₂— or —C(O)—, preferably —CH₂—; Q¹⁰¹ is aryl orheteroaryl, wherein aryl or heteroaryl are optionally substituted withone or more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and—S(O)₂R⁴¹; Q¹⁰⁵ is hydrogen, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and—S(O)₂R⁴¹; and Q¹¹² is hydrogen, fluoro, chloro, lower alkyl or fluorosubstituted lower alkyl, wherein R⁴¹ is as defined for Formula Ig.

In one embodiment of compounds of Formula IIk, A₁₂ is —CH₂— or —C(O)—,preferably —CH₂—; Q¹⁰¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹,—NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹, NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as asubstituent of Q¹⁰¹, or as a substituent of lower alkyl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,—NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q¹⁰⁵ ishydrogen, —CN, —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₁₄ is a bond, —NR³⁹—, —S—, —O—,—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, —C(O)NR³⁹—,—S(O)₂NR³⁹—, —CH₂NR³⁹—, —CH(R⁴⁰NR³⁹—, —NR³⁹C(O)—, or —NR³⁹S(O)₂—; andQ¹¹² is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, —NR⁴⁴R⁴⁴, —OR⁴⁴, or —SR⁴⁴, wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴⁴ areas defined for Formula II.

In one embodiment of compounds of Formula IIk, A₁₂ is —CH₂—; Q¹⁰¹ isaryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q¹⁰⁵ ishydrogen, —CN, fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, or fluoro substituted lower alkoxy; M₁₄ is—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, or —NR³⁹CH(R⁴⁰)—; and Q¹¹² is hydrogen, fluoro,chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, orfluoro substituted lower alkoxy.

In one embodiment, further to any of the embodiments of Formula IIkabove, each occurrence of R⁴¹ is R⁴² as defined for Formula Ig.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula IIm,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₁₃ is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S(O)—, —S(O)₂—, —NR²¹—, and —O—;    -   Q¹¹⁵ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —NH₂,        —NO₂, —CN, —NHC(O)NH₂—, —NHC(S)NH₂—, —NHS(O)₂NH₂—, —C(O)NH₂—,        —C(S)NH₂—, —S(O)₂NH₂—, —NR²⁴R²⁵, —NHR²³, —OR²³, —SR²³, —C(O)R²³,        —C(S)R²³, —S(O)R²³, —S(O)₂R²³, —C(O)NHR²³, —C(O)NR²³R²³,        —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³, —S(O)₂NR²³R²³,        —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³, —NHS(O)₂R²³,        —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,        —NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,        —NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,        —NR²³S(O)₂NH₂—, —NR²³S(O)₂NHR²³, —NHS(O)₂NR²³R²³, and        —NR²³S(O)₂NR²³R²³;    -   M₁₅, Q¹¹¹, and Q¹²⁴ are as defined for Formula II; and    -   R¹⁹, R²⁰, R²¹, R²³, R²⁴, and R²⁵ are as defined for Formula Ib.

In one embodiment of compounds of Formula IIm, M₁₅ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s), preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—, wherein R³⁹ is hydrogen or lower alkyl and R⁸⁰ ishydrogen, lower alkyl or fluoro substituted lower alkyl, preferablyhydrogen. In one embodiment, A₁₃ is —CR¹⁹R²⁰— or —C(O)—, preferably—CH₂— or —C(O)—. In one embodiment, Q¹¹¹ is optionally substituted loweralkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ and Q¹¹⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³. Further to any of the above embodiments, Q¹²⁴ is hydrogen,fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment of compounds of Formula IIm, M₁₅ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—, and A₁₃ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—. In one embodiment, M₁₅ is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or —NR³⁹(CR⁸⁰R⁸⁰)₂—; A₁₃ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—;Q¹¹¹ is optionally substituted lower alkyl, aryl or heteroaryl, whereinaryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³;and Q¹¹⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³. In one embodiment, M₁₅ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—; A₁₃ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—; Q¹¹¹ is optionally substituted lower alkyl, aryl or heteroaryl,wherein aryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³;Q¹¹⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; and Q¹²⁴ is hydrogen,fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment of compounds of Formula IIm, M₁₅ is —NR³⁹CH₂— or—NR³⁹—(CH₂)₂—; A₁₃ is —CH₂— or —C(O)—, preferably —CH₂—; Q¹¹¹ is aryl orheteroaryl, wherein aryl or heteroaryl are optionally substituted withone or more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and—S(O)₂R⁴¹; Q¹¹⁵ is hydrogen, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴², —NR⁴²R⁴², —OR⁴² and—S(O)₂R⁴²; and Q¹²⁴ is hydrogen, fluoro, chloro, lower alkyl or fluorosubstituted lower alkyl, wherein R⁴¹ is as defined for Formula Ig.

In one embodiment of compounds of Formula IIm, A₁₃ is —CH₂— or —C(O)—,preferably —CH₂—; Q¹¹¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹,—NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as asubstituent of Q¹¹, or as a substituent of lower alkyl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,—NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q¹¹⁵ ishydrogen, —CN, —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₁₅ is a bond, —NR³⁹—, —S—, —O—,—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, —C(O)NR³⁹—,—S(O)₂NR³⁹—, —CH₂NR³⁹—, —CH(R⁴⁰)NR³⁹—, —NR³⁹C(O)—, or —NR³⁹S(O)₂—; andQ¹²⁴ is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, —NR⁴⁴R⁴⁴, —OR⁴⁴, or —SR⁴⁴, wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴⁴ areas defined for Formula II.

In one embodiment of compounds of Formula IIm, A₁₃ is —CH₂—; Q¹¹¹ isaryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q¹¹⁵ ishydrogen, —CN, fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, or fluoro substituted lower alkoxy; M₁₅ is—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, or —NR³⁹CH(R⁴⁰)—; and Q¹²⁴ is hydrogen, fluoro,chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, orfluoro substituted lower alkoxy.

In one embodiment, further to any of the embodiments of Formula IImabove, each occurrence of R⁴¹ is R⁴² as defined for Formula Ig.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula IIn,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₁₄ is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S(O)—, —S(O)₂—, —NR²¹—, and —O—;    -   Q¹²⁵ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —NH₂,        —NO₂, —CN, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(O)NH₂,        —C(S)NH₂, —S(O)₂NH₂, —NR²⁴R²⁵, —NHR²³, —OR²³, —SR²³, —C(O)R²³,        —C(S)R²³, —S(O)R²³, —S(O)₂R²³, —C(O)NHR²³, —C(O)NR²³R²³,        —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³, —S(O)₂NR²³R²³,        —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³, —NHS(O)₂R²³,        —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,        —NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,        —NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,        —NR²³S(O)₂NH₂, —NR²³S(O)₂NHR²³, —NHS(O)₂NR²³R²³, and        —NR²³S(O)₂NR²³R²³    -   M₁₆, Q¹²¹, and Q¹³² are as defined for Formula II; and    -   R¹⁹, R²⁰, R²¹, R²³, R²⁴, and R²⁵ are as defined for Formula Ib.

In one embodiment of compounds of Formula IIn, M₁₆ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR^(s)OR⁸⁰)₂—, wherein R³⁹ is hydrogen or lower alkyl and R⁸⁰ ishydrogen, lower alkyl or fluoro substituted lower alkyl, preferablyhydrogen. In one embodiment, A₁₄ is —CR¹⁹R²⁰— or —C(O)—, preferably—CH₂— or —C(O)—. In one embodiment, Q¹²¹ is optionally substituted loweralkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ and Q¹²⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³. Further to any of the above embodiments, Q¹³² is hydrogen,fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment of compounds of Formula IIn, M₁₆ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—, and A₁₄ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—. In one embodiment, M₁₆ is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or —NR³⁹(CR⁸⁰R⁸⁰)₂—; A₁₄ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—;Q¹²¹ is optionally substituted lower alkyl, aryl or heteroaryl, whereinaryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³;and Q¹²⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ In one embodiment, M₁₆ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—; A₁₄ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—; Q¹²¹ is optionally substituted lower alkyl, aryl or heteroaryl,wherein aryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³;Q¹²⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; and Q¹³² is hydrogen,fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.

In one embodiment of compounds of Formula IIn, M₁₆ is —NR³⁹CH₂— or—NR³⁹—(CH₂)₂—; A₁₄ is —CH₂— or —C(O)—, preferably —CH₂—; Q¹²¹ isoptionally substituted lower alkyl, aryl or heteroaryl, wherein aryl orheteroaryl are optionally substituted with one or more substituentsselected from the group consisting of halogen, lower alkyl, fluorosubstituted lower alkyl, —NHR⁴², —NR⁴²R⁴², —OR⁴² and —S(O)₂R⁴²; Q¹²⁵ ishydrogen, —CN, fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and—S(O)₂R⁴¹; and Q¹³² is hydrogen, fluoro, chloro, lower alkyl or fluorosubstituted lower alkyl, wherein R⁴¹ is as defined for Formula Ig.

In one embodiment of compounds of Formula IIn, A₁₄ is —CH₂— or —C(O)—,preferably —CH₂—; Q¹²¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹,—NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as asubstituent of Q¹²¹, or as a substituent of lower alkyl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,—NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q¹²⁵ ishydrogen, —CN, —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₁₆ is a bond, —NR³⁹—, —S—, —O—,—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, —C(O)NR³⁹—,—S(O)₂NR³⁹—, —CH₂NR³⁹—, —CH(R⁴⁰)NR³⁹—, —NR³⁹C(O)—, or —NR³⁹S(O)₂—; andQ¹³² is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, —NR⁴⁴R⁴⁴, —OR⁴⁴, or —SR⁴⁴, wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴⁴ areas defined for Formula II.

In one embodiment of compounds of Formula IIn, A₁₄ is —CH₂—; Q¹²¹ isaryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q²⁵ ishydrogen, —CN, fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, or fluoro substituted lower alkoxy; M₁₆ is—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, or —NR³⁹CH(R⁴⁰)—; and Q¹³² is hydrogen, fluoro,chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, orfluoro substituted lower alkoxy.

In one embodiment, further to any of the embodiments of Formula IInabove, each occurrence of R⁴¹ is R⁴² as defined for Formula Ig.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula IIo,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₁₅ is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S(O)—, —S(O)₂—, —NR²—, and —O—;    -   Q¹³⁵ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —NH₂,        —NO₂, —CN, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(O)NH₂,        —C(S)NH₂, —S(O)₂NH₂, —NR²⁴R²⁵, —NHR²³, —OR²³, —SR²³, —C(O)R²³,        —C(S)R²³, —S(O)R²³, —S(O)₂R²³, —C(O)NHR²³, —C(O)NR²³R²³,        —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³, —S(O)₂NR²³R²³,        —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³, —NHS(O)₂R²³,        —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,        —NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,        —NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,        —NR²³S(O)₂NH₂, —NR²³S(O)₂NHR²³, —NHS(O)₂NR²³R²³, and        —NR²³S(O)₂NR²³R²³;    -   M₁₇, Q¹³¹, and Q¹⁴⁴ are as defined for Formula II; and

R¹⁹, R²⁰, R²¹, R²³, R²⁴, and R²⁵ are as defined for Formula Ib.

In one embodiment of compounds of Formula IIo, M₁₇ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR^(s)OR⁸⁰)₂—, wherein R³⁹ is hydrogen or lower alkyl and R⁸⁰ ishydrogen, lower alkyl or fluoro substituted lower alkyl, preferablyhydrogen. In one embodiment, A₁₅ is —CR¹⁹R²⁰— or —C(O)—, preferably—CH₂— or —C(O)—. In one embodiment, Q¹³¹ is optionally substituted loweralkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ and Q¹³⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³. Further to any of the above embodiments, Q¹⁴⁴ is hydrogen,fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl.

In one embodiment of compounds of Formula IIo, M₁₇ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰—,—NR³⁹(CR⁸⁰R⁸⁰)₂—, and A₁₅ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—. In one embodiment, M₁₇ is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰—, —NR³⁹(CR⁸⁰R⁸⁰)₂—; A₁₅ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—;Q¹³¹ is optionally substituted lower alkyl, aryl or heteroaryl, whereinaryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³;and Q¹³⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ In one embodiment, M₁₇ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰—,—NR³⁹(CR⁸⁰R⁸⁰)₂—; A₁₅ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—; Q¹³¹ is optionally substituted lower alkyl, aryl or heteroaryl,wherein aryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³,Q¹³⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; and Q¹⁴⁴ is hydrogen,fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl.

In one embodiment of compounds of Formula IIo, M₁₇ is —NR³⁹CH₂— or—NR³⁹—(CH₂)₂—; A₁₅ is —CH₂— or —C(O)—, preferably —CH₂—; Q¹³¹ is aryl orheteroaryl, wherein aryl or heteroaryl are optionally substituted withone or more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴², —NR⁴²R⁴², —OR⁴² and—S(O)₂R⁴²; Q¹³⁵ is hydrogen, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and—S(O)₂R⁴¹; and Q¹⁴⁴ is hydrogen, fluoro, chloro, lower alkyl, or fluorosubstituted lower alkyl, wherein R⁴¹ is as defined for Formula Ig.

In one embodiment of compounds of Formula IIo, A₁₅ is —CH₂— or —C(O)—,preferably —CH₂—; Q¹³¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹,—NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as asubstituent of Q¹³¹, or as a substituent of lower alkyl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,—NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q¹³⁵ ishydrogen, —CN, —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₁₅ is a bond, —NR³⁹—, —S—, —O—,—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, —C(O)NR³⁹—,—S(O)₂NR³⁹—, —CH₂NR³⁹—, —CH(R⁴⁰)NR³⁹—, —NR³⁹C(O)—, or —NR³⁹S(O)₂—; andQ¹⁴⁴ is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, —NR⁴⁴R⁴⁴, —OR⁴⁴, or —SR⁴⁴, wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴⁴ areas defined for Formula II.

In one embodiment of compounds of Formula IIo, A₁₅ is —CH₂—; Q¹³¹ isaryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q¹³⁵ ishydrogen, —CN, fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, or fluoro substituted lower alkoxy; M₁₅ is—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, or —NR³⁹CH(R⁴⁰)—; and Q¹⁴⁴ is hydrogen, fluoro,chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, orfluoro substituted lower alkoxy.

In one embodiment, further to any of the embodiments of Formula Hoabove, each occurrence of R⁴¹ is R⁴² as defined for Formula Ig.

In one embodiment, a compound of Formula II has a structure according tothe following sub-generic structure, Formula IIp,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   A₁₆ is selected from the group consisting of —CR¹⁹R²⁰—, —C(O)—,        —C(S)—, —S—, —S(O)—, —S(O)₂—, —NR²¹—, and —O—;    -   Q¹⁴⁵ is selected from the group consisting of hydrogen, halogen,        optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —NH₂,        —NO₂, —CN, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(O)NH₂,        —C(S)NH₂, —S(O)₂NH₂, —NR²⁴R²⁵, —NHR²³, —OR²³, —SR²³, —C(O)R²³,        —C(S)R²³, —S(O)R²³, —S(O)₂R²³, —C(O)NHR²³, —C(O)NR²³R²³,        —C(S)NHR²³, —C(S)NR²³R²³, —S(O)₂NHR²³, —S(O)₂NR²³R²³,        —NHC(O)R²³, —NR²³C(O)R²³, —NHC(S)R²³, —NR²³C(S)R²³, —NHS(O)₂R²³,        —NR²³S(O)₂R²³, —NHC(O)NHR²³, —NR²³C(O)NH₂, —NR²³C(O)NHR²³,        —NHC(O)NR²³R²³, —NR²³C(O)NR²³R²³, —NHC(S)NHR²³, —NR²³C(S)NH₂,        —NR²³C(S)NHR²³, —NHC(S)NR²³R²³, —NR²³C(S)NR²³R²³, —NHS(O)₂NHR²³,        —NR²³S(O)₂NH₂, —NR²³S(O)₂NHR²³, —NHS(O)₂NR²³R²³, and        —NR²³S(O)₂NR²³R²³    -   M₁₈, Q¹⁴¹, and Q¹⁵² are as defined for Formula II; and

R¹⁹, R²⁰, R²¹, R²³, R²⁴, and R²⁵ are as defined for Formula Ib;

-   -   provided, however, that the compound is not H or

In one embodiment of compounds of Formula IIp, M₁₈ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR^(s)OR⁸⁰)₂—, wherein R³⁹ is hydrogen or lower alkyl and R⁸⁰ ishydrogen, lower alkyl or fluoro substituted lower alkyl, preferablyhydrogen. In one embodiment, A₁₆ is —CR¹⁹R²⁰— or —C(O)—, preferably—CH₂— or —C(O)—. In one embodiment, Q¹⁴¹ is optionally substituted loweralkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ and Q¹⁴⁵ is hydrogen, —OR²³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and—S(O)₂R²³. Further to any of the above embodiments, Q¹⁵² is hydrogen,fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl.

In one embodiment of compounds of Formula IIp, M₁₈ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—, and A₁₆ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—. In one embodiment, M₁₈ is —(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or —NR³⁹(CR⁸⁰R⁸⁰)₂—; A₁₆ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or —C(O)—;Q¹⁴¹ is optionally substituted lower alkyl, aryl or heteroaryl, whereinaryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³;and Q¹⁴⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³ In one embodiment, M₁₈ is—(CR¹⁹R²⁰)_(t)—NR²⁶—(CR¹⁹R²⁰)_(s)— or—(CR¹⁹R²⁰)_(t)—NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, preferably —NR²⁶—(CR¹⁹R²⁰)_(s)—or —NR²⁶C(O)—(CR¹⁹R²⁰)_(s)—, more preferably —NR³⁹CR⁸⁰R⁸⁰— or—NR³⁹(CR⁸⁰R⁸⁰)₂—; A₁₆ is —CR¹⁹R²⁰— or —C(O)—, preferably —CH₂— or—C(O)—; Q¹⁴¹ is optionally substituted lower alkyl, aryl or heteroaryl,wherein aryl or heteroaryl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, lower alkyl,fluoro substituted lower alkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³;Q¹⁴⁵ is hydrogen, —OR²³, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR²³, —NR²³R²³, —OR²³ and —S(O)₂R²³; and Q¹⁵² is hydrogen,fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl.

In one embodiment of compounds of Formula IIp, M₁₈ is —NR³⁹CH₂— or—NR³⁹—(CH₂)₂—; A₁₆ is —CH₂— or —C(O)—, preferably —CH₂—; Q¹⁴¹ is aryl orheteroaryl, wherein aryl or heteroaryl are optionally substituted withone or more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and—S(O)₂R⁴¹; Q¹⁴⁵ is hydrogen, —CN, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from the group consisting of halogen,lower alkyl, fluoro substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and—S(O)₂R⁴¹; and Q¹⁵² is hydrogen, fluoro, chloro, lower alkyl, or fluorosubstituted lower alkyl, wherein R⁴¹ is as defined for Formula Ig.

In one embodiment of compounds of Formula IIp, A₁₆ is —CH₂— or —C(O)—,preferably —CH₂—; Q¹⁴¹ is aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹,—NR⁴¹R⁴¹, —NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, halogen, lower alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino,di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as asubstituent of Q¹⁴¹, or as a substituent of lower alkyl are optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, —NH₂, —CN, —NO₂, —S(O)₂NH₂, —C(O)NH₂, —OR⁴², —SR⁴²,—NHR⁴², —NR⁴²R⁴², —NR³⁹C(O)R⁴², —NR³⁹S(O)₂R⁴², —S(O)₂R⁴², halogen, loweralkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q¹⁴⁵ ishydrogen, —CN, —OR⁴¹, —SR⁴¹, —S(O)R⁴¹, —S(O)₂R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹,—NR³⁹C(O)R⁴¹, —NR³⁹S(O)₂R⁴¹, fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroarylare optionally substituted with one or more substituents selected fromthe group consisting of halogen, lower alkyl, fluoro substituted loweralkyl, —NHR⁴¹, —NR⁴¹R⁴¹, and —OR⁴¹; M₁₈ is a bond, —NR³⁹—, —S—, —O—,—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, —NR³⁹CH(R⁴⁰)—, —SCH₂—, —OCH₂—, —C(O)NR³⁹—,—S(O)₂NR³⁹—, —CH₂NR³⁹—, —CH(R⁴⁰)NR³⁹—, —NR³⁹C(O)—, or —NR³⁹S(O)₂—; andQ¹⁵² is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, —NR⁴⁴R⁴⁴, —OR⁴⁴, or —SR⁴⁴, wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴⁴ areas defined for Formula II.

In one embodiment of compounds of Formula IIp, A₁₆ is —CH₂—; Q¹⁴¹ isaryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q¹⁴⁵ ishydrogen, —CN, fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, or fluoro substituted lower alkoxy; M₁₈ is—NR³⁹CH₂—, —NR³⁹CH₂CH₂—, or —NR³⁹CH(R⁴⁰)—; and Q¹⁵² is hydrogen, fluoro,chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, orfluoro substituted lower alkoxy.

In one embodiment, further to any of the embodiments of Formula IIpabove, each occurrence of R⁴¹ is R⁴² as defined for Formula Ig.

In one embodiment of compounds of Formula IIp, M₁₈ is —NH—CH₂— or—NH—(CH₂)₂—, preferably —NH—CH₂—; A₁₆ is —CH₂— or —C(O)—, preferably—CH₂—; Q¹⁴¹ is aryl or heteroaryl, wherein aryl or heteroaryl areoptionally substituted with 1 or 2 substituents selected from the groupconsisting of fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, fluoro substituted lower alkoxy, andheterocycloalkyl; Q¹⁴⁵ is hydrogen, —CN, fluoro, chloro, lower alkyl,fluoro substituted lower alkyl, lower alkoxy, or fluoro substitutedlower alkoxy, preferably hydrogen, —CN, or chloro; and Q¹⁵² is hydrogen,fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl,preferably hydrogen or chloro, more preferably chloro.

In one embodiment, the compound of Formula Ih is selected from the groupconsisting of

-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine    (P-0156),-   [4-Ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine    (P-0162),-   (4-Fluoro-benzyl)-[4-methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine    (P-0163),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl-amine    (P-0164),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-2-ylmethyl-amine    (P-0167),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amine    (P-0168),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2-ylmethyl)-amine    (P-0171),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(1,5-dimethyl-1H-pyrazol-3-ylmethyl)-amine    (P-0172),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0173),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-amine(P-0175),-   [2-(4-Fluoro-benzylamino)-thiazol-5-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-0177),-   {2-[(4-Chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-0178),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-thiazol-2-ylmethyl-amine    (P-0189),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine    (P-0190),-   Benzyl-[4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine    (P-0192),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-methoxy-benzyl)-amine    (P-0193),-   (4-Chloro-benzyl)-[4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine    (P-0194),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine    (P-0195),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5-ylmethyl)-amine    (P-0196),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H-imidazol-4-ylmethyl)-amine    (P-0197),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-2H-pyrazol-3-ylmethyl)-amine    (P-0198),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-2-ylmethyl)-amine    (P-0199),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-4-ylmethyl)-amine    (P-0200),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-thiazol-4-ylmethyl)-amine    (P-0201),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-methyl-thiazol-5-ylmethyl)-amine    (P-0202),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-chloro-pyridin-2-ylmethyl)-amine    (P-0203),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5-ylmethyl)-amine    (P-0204),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H-imidazol-4-ylmethyl)-amine    (P-0205),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-2-ylmethyl)-amine    (P-0206),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3-ylmethyl)-amine    (P-0207),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4,5-dimethyl-thiophen-2-ylmethyl)-amine    (P-0208),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,5-dimethyl-thiophen-3-ylmethyl)-amine    (P-0209),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine    (P-0231),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl-amine    (P-0236),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amine    (P-0237),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-chloro-pyridin-4-ylmethyl)-amine    (P-0238),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(1-ethyl-1H-pyrazol-4-ylmethyl)-amine    (P-0239),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-2-ylmethyl)-amine    (P-0240),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3-ylmethyl)-amine    (P-0241),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0242),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-6-fluoro-benzyl)-amine    (P-0243),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-phenethyl-amine    (P-0244),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-difluoro-benzyl)-amine    (P-0245),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-fluoro-benzyl)-amine    (P-0246),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methoxy-pyridin-3-ylmethyl)-amine    (P-0247),-   (2-Chloro-benzyl)-[4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine    (P-0248),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-benzyl)-amine    (P-0249),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-4-fluoro-benzyl)-amine    (P-0250),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-2-ylmethyl)-amine    (P-0251),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-morpholin-4-yl-pyridin-2-ylmethyl)-amine    (P-0252),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3,5-dichloro-pyridin-4-ylmethyl)-amine    (P-0253),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0254),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2-ylmethyl)-amine    (P-0255),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine    (P-0290), and    all salts, prodrugs, tautomers, and isomers thereof.

In one embodiment, a compound of Formula I has a structure according tothe following sub-generic structure, Formula III,

all salts, prodrugs, tautomers, and isomers thereof,wherein:

-   -   L₄ is —CH₂—, —CH₂CH₂—, —CH(R⁴⁰)—, —C(O)—, or —C(O)NH—;    -   R⁸¹ is selected from the group consisting of hydrogen, —OR⁴¹,        —CN, fluoro, chloro, lower alkyl, fluoro substituted lower        alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,        wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are        optionally substituted with one or more substituents selected        from the group consisting of halogen, lower alkyl, fluoro        substituted lower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and —S(O)₂R⁴¹;    -   R⁸² is selected from the group consisting of hydrogen,        C₁₋₃alkyl, fluoro substituted C₂₋₃alkyl, OH, C₁₋₃alkoxy, and        fluoro substituted C₁₋₃alkoxy;    -   R⁸³ is heterocycloalkyl, heteroaryl, or

in which

indicates the attachment point of R⁸³ to L₄ of Formula III, whereinheterocycloalkyl or heteroaryl are optionally substituted with one ormore substituents selected from the group consisting of halogen, loweralkyl, fluoro substituted lower alkyl, cycloalkylamino, —NHR⁴¹,—NR⁴¹R⁴¹, —OR⁴¹ and —S(O)₂R⁴¹;

-   -   R⁹², R⁹³, R⁹⁴, R⁹⁵, and R⁹⁶ are independently selected from the        group consisting of hydrogen, halogen, lower alkyl, fluoro        substituted lower alkyl, cycloalkylamino, —NHS(O)₂R⁴¹,        —NHC(O)R⁴¹, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and —S(O)₂R⁴¹; and    -   R⁴⁰ and R⁴¹ are as defined for Formula Ig; provided, however,        that the compound is not

In one embodiment of compounds of Formula III, L₄ is —CH₂—, —CH₂CH₂—,—CH(CH₃)— or —C(O)—, R⁸¹ is hydrogen, fluoro, chloro, —CN, lower alkyl,fluoro substituted lower alkyl, lower alkoxy, or fluoro substitutedlower alkoxy, R⁸² is hydrogen, R⁸³ is

wherein R⁹², R⁹³, R⁹⁴, R⁹⁵, and R⁹⁶ are independently hydrogen, fluoro,chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, orfluoro substituted lower alkoxy, provided, however, that when R⁹⁴ isfluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, or fluoro substituted lower alkoxy, at least one of R⁹², R⁹³,R⁹⁵, and R⁹⁶ is fluoro, chloro, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, or fluoro substituted lower alkoxy.

In one embodiment of compounds of Formula III, L₄ is —CH₂—, —CH₂CH₂—,—CH(CH₃)— or —C(O)—, R⁸¹ is hydrogen, fluoro, chloro, —CN, methyl, ormethoxy, preferably hydrogen, chloro, —CN, or methyl, R⁸² is hydrogen,R⁸³ is

wherein R⁹², R⁹³R⁹⁴, R⁹⁵, and R⁹⁶ are independently hydrogen, fluoro,chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxyor trifluoromethoxy, preferably hydrogen, chloro, methyl,trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy, provided,however, that when R⁹⁴ is fluoro, chloro, methyl, ethyl,trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy,at least one of R⁹², R⁹³, R⁹⁵, and R⁹⁶ is fluoro, chloro, methyl, ethyl,trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.

In one embodiment of compounds of Formula III, L₄ is —CH₂—, R⁸¹ isfluoro, chloro, —CN, methyl, or methoxy, preferably chloro, —CN, ormethyl, R⁸² is hydrogen, R⁸³ is

wherein R⁹⁴ is hydrogen and R⁹², R⁹³, R⁹⁵, and R⁹⁶ are independentlyhydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, ethoxy,difluoromethoxy or trifluoromethoxy.

In one embodiment of compounds of Formula III, L₄ is —CH₂—, —CH₂CH₂—,—C(O)—, or —CH(CH₃)—, preferably —CH₂— or —C(O)—, R⁸¹ is hydrogen,fluoro, R⁸² is hydrogen, R⁸³ is

wherein R⁹² is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy,ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro,methyl, or trifluoromethyl, and R⁹³, R⁹⁴, R⁹⁵, and R⁹⁶ are independentlyhydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy,difluoromethoxy, or trifluoromethoxy, preferably hydrogen or fluoro. Inone embodiment, L₄ is —CH₂—, —C(O)—, or —CH(CH₃)—, R⁸¹ is hydrogen, R⁸²is hydrogen, R⁹² is fluoro, chloro, methyl, ethyl, trifluoromethyl,methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferablyfluoro, methyl, or trifluoromethyl, and R⁹³, R⁹⁴, R⁹⁵, and R⁹⁶ arehydrogen. In one embodiment, L₄ is —CH₂—, —C(O)—, or —CH(CH₃)—, R⁸¹ ishydrogen, R⁸² is hydrogen, R⁹² is fluoro, chloro, methyl, ethyl,trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy,preferably fluoro, methyl, or trifluoromethyl, R⁹⁴, R⁹⁵, and R⁹⁶ arehydrogen, and R⁹³ is fluoro, chloro, methyl, ethyl, trifluoromethyl,methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferablyfluoro, chloro, trifluoromethyl or methoxy, more preferably fluoro. Inone embodiment, L₄ is —CH₂—, —C(O)—, or —CH(CH₃)—, R⁸¹ is hydrogen, R⁸²is hydrogen, R⁹² is fluoro, chloro, methyl, ethyl, trifluoromethyl,methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferablyfluoro, methyl, or trifluoromethyl, R⁹³, R⁹⁵, and R⁹⁶ are hydrogen, andR⁹⁴ is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy,difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro, methylor trifluoromethyl, more preferably fluoro. In one embodiment, L₄ is—CH₂CH₂— or —C(O)—, R⁸¹ is hydrogen, R⁸² is hydrogen, R⁹², R⁹⁵, and R⁹⁶are hydrogen, R⁹³ is hydrogen, fluoro, chloro, methyl, ethyl,trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy,preferably hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy,or trifluoromethoxy, more preferably fluoro, chloro, trifluoromethyl ormethoxy, and R⁹⁴ is hydrogen, fluoro, or chloro, provided, however, thatwhen L₄ is —C(O)— and R⁹⁴ is fluoro or chloro, R⁹³ is not hydrogen. Inone embodiment, L₄ is —CH₂CH₂—, R⁸¹ is hydrogen, R⁸² is hydrogen, R⁹²,R⁹⁴, R⁹⁵, and R⁹⁶ are hydrogen, and R⁹³ is hydrogen, fluoro, chloro,methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, ortrifluoromethoxy, preferably hydrogen or fluoro. In one embodiment, L₄is —C(O)—, R⁸¹ is hydrogen, R⁸² is hydrogen, R⁹², R⁹⁵, and R⁹⁶ arehydrogen, R⁹³ is fluoro, chloro, methyl, ethyl, trifluoromethyl,methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferablyfluoro, chloro, trifluoromethyl or methoxy, and R⁹⁴ is hydrogen, fluoro,or chloro.

In one embodiment of compounds of Formula III, R⁸³ is pyrrolidine,morpholine, pyridine, pyrimidine, pyrazine, pyrazole, isoxazole,imidazol, or benzimidazole, wherein R⁸³ is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,cycloalkylamino, —NHR⁴¹, —NR⁴¹R⁴¹, —OR⁴¹ and —S(O)₂R⁴¹, preferablywherein R⁸³ is optionally substituted with 1 or 2 substituentsindependently selected from fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,or cycloalkylamino, more preferably fluoro, chloro, methyl,trifluoromethyl, methoxy or morpholine.

In one embodiment of compounds of Formula III, L₄ is —CH₂—, —CH₂CH₂—,—CH(CH₃)— or —C(O)—, preferably —CH₂—, —CH₂CH₂—, or —C(O)—, R⁸¹ ishydrogen, fluoro, chloro, —CN, lower alkyl, fluoro substituted loweralkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferablyhydrogen, chloro, methyl or —CN, R⁸² is hydrogen, and R⁸³ ispyrrolidine, morpholine, pyridine, pyrimidine, pyrazine, pyrazole,isoxazole, imidazole, or benzimidazole, wherein R⁸³ is optionallysubstituted with 1 or 2 substituents independently selected from fluoro,chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy,fluoro substituted lower alkoxy, or cycloalkylamino, preferably fluoro,chloro, methyl, trifluoromethyl, methoxy or morpholine.

In one embodiment of compounds of Formula III, the compound is selectedfrom the group consisting of:

-   Pyridin-3-ylmethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0094),-   (5-Methyl-isoxazol-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0095),-   (2-Pyrrolidin-1-yl-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0096),-   [1-(4-Methanesulfonyl-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0097),-   (2-Morpholin-4-yl-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0099),-   3,4-Dichloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0100),-   2-Chloro-4-fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0101),-   2,5-Dimethyl-2H-pyrazole-3-carboxylic acid    [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide    (P-0102),-   Thiophene-2-carboxylic acid    [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide    (P-0103),-   2-Methoxy-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide    (P-0104),-   N-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide    (P-0105),-   Pyrazine-2-carboxylic acid    [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide    (P-0106),-   Pyridine-2-carboxylic acid    [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide    (P-0107),-   6-Methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-nicotinamide    (P-0108),-   4-Fluoro-3-methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0109),-   5-Methyl-pyrazine-2-carboxylic acid    [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide    (P-0110),-   3-Chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0111),-   4-Fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethyl-benzamide    (P-0112),-   N-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethoxy-benzamide    (P-0113),-   N-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethyl-benzamide    (P-0114),-   3-Chloro-4-fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0115),-   3,4-Difluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0116),-   2-Chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0117),-   5-Fluoro-2-methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0118),-   2-Fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0119),-   3-Methoxy-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0120),-   3-Fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0121),-   3-Methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0122),-   2-Chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide    (P-0123),-   ((R)-1-Phenyl-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0125),-   (3-Morpholin-4-yl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0126),-   [1-(2-Fluoro-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0127),-   [2-(3-Fluoro-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0128),-   (3-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0129),-   (1-Methyl-1H-imidazol-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0130),-   (1,5-Dimethyl-1H-pyrazol-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0131),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0181),-   [5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0182),-   (3-Chloro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0183),-   (2-Chloro-6-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0210),-   Phenethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0211),-   (2,4-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0212),-   (2-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0213),-   (3-Bromo-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0214),-   (2-Methoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0215),-   (2-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0216),-   (2-Methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0217),-   (1-Methyl-1H-benzoimidazol-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0218),-   (6-Methoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0219),-   (1H-Benzoimidazol-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]amine    (P-0220),-   (2-Chloro-4-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0221),-   (5-Methoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0222),-   (3-Fluoro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0223),-   (6-Methoxy-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0224),-   (4-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0225),-   [5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0226),-   (3,5-Dichloro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0227),-   (6-Morpholin-4-yl-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0228),-   (3-Fluoro-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0229),-   (5-Fluoro-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0230),-   (3-Chloro-pyridin-4-ylmethyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0235),-   3-{6-[(3-Chloro-pyridin-4-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0256),-   3-[6-(4-Chloro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0257),-   Propane-1-sulfonic acid    (2,4-difluoro-3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-phenyl)-amide    (P-0258),-   Propane-1-sulfonic acid    (3-{[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-2,4-difluoro-phenyl)-amide    (P-0259),-   3-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0269),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-fluoro-benzyl)-amine    (P-0270),-   3-[6-(2-Fluoro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0271),-   (2-Fluoro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0272),-   3-{6-[(6-Trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0273),-   3-[6-(2-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0274),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0275),-   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0276),-   3-[6-(2,6-Difluoro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0277),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,6-difluoro-benzyl)-amine    (P-0278),-   (2-Chloro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0279),-   (2-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0280),-   3-[6-(2-Chloro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0281),-   (6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0282),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine    (P-0283),-   3-{6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0284),-   (2-Methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0285),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-methoxy-pyridin-3-ylmethyl)-amine    (P-0286),-   3-{6-[(2-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0287),-   (2-Ethoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0288),-   (2,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0296),-   (2,5-Difluoro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0297),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,5-difluoro-benzyl)-amine    (P-0298),-   3-[6-(2,5-Difluoro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0299),-   3-[6-(2-Trifluoromethoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrollamino[2,3-b]pyridine-5-carbonitrile    (P-0321),-   [5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethoxy-benzyl)-amine    (P-0322),-   3-[6-(2-Ethoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0323),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine    (P-0324),-   [5-(5-Fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0325),-   [5-(5-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0326),-   (2-Chloro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0327),-   (2-Chloro-benzyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0328),-   (2,5-Difluoro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0329),-   (2,5-Difluoro-benzyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0330),-   [5-(5-Fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine    (P-0331),-   (6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0332),-   (2,6-Difluoro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0333),-   (2,6-Difluoro-benzyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0334),-   (2-Methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0336),-   3-[6-(2-Methoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0337),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-difluoromethoxy-benzyl)-amine    (P-0338),-   3-[6-(2-Difluoromethoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0339),-   (2,6-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0340),-   (2,6-Difluoro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0341),-   (2,4-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0342),-   (3-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0343),-   (2-Fluoro-4-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0344),-   (4-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0345),-   (3-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0346),-   (2-Morpholin-4-yl-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0347),-   (4-Chloro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0348),-   (2-Chloro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0349),-   (2-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0350),-   (2,3-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0351),-   (2-Fluoro-3-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0352),-   Dimethyl-(5-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyrimidin-2-yl)-amine    (P-0353),-   (3-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0354),-   (5-Fluoro-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0355),-   (3,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0356),-   (2-Propoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0357),-   (2-Morpholin-4-yl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0358),-   (2-Chloro-3-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0359),-   (2-Fluoro-6-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0360),-   [2-(2-Morpholin-4-yl-ethoxy)-benzyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0361),-   (2,3-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0362),-   (2-Chloro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0363),-   (2-Chloro-5-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0364),-   (2-Fluoro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0365),-   (5-Fluoro-2-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0366),-   (2-Difluoromethoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0367),-   (2-Fluoro-4-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0368),-   [2-(3-Dimethylamino-propoxy)-benzyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0369),-   (2,6-Dimethoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0370),-   (2-Fluoro-5-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0371),-   (4-Fluoro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0372),-   (3-Chloro-5-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0373),-   (6-Cyclopentyloxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0374),-   (5-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0375),-   [5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-[2-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-amine    (P-0376),-   Propane-1-sulfonic acid    (2-fluoro-3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-phenyl)-amide    (P-0377),-   (2,5-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0380),-   Pyrimidin-5-ylmethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0381),-   (5-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0382),-   (2-Ethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0383),-   2,2-Dimethyl-N-(3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-propionamide    (P-0384),-   Methyl-(3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-amine    (P-0385),-   Methyl-(5-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyrimidin-2-yl)-amine    (P-0386),-   (2-Chloro-4-methanesulfonyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0387),-   {5-[1-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-amine    (P-0388),-   (5-Fluoro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0397),

Dimethyl-(3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-amine(P-0399),

-   (5-Chloro-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0400),-   (2-Methoxy-pyrimidin-5-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0401),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-amine    (P-0409),-   1-(3-Fluoro-phenyl)-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-urea    (P-0412), and    all salts, prodrugs, tautomers, and isomers thereof.

In one embodiment, a compound of the invention is:

-   (4-Chloro-benzyl)-[6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridazin-3-yl]-amine    (P-0092),-   (4-Morpholin-4-ylmethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0093),-   (2-Methoxy-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0098),-   [4-Chloro-1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-amine    (P-0166),-   ((2,2-Difluoro-benzo[1,3]dioxol-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0398); or    all salts, prodrugs, tautomers, and isomers thereof.

In certain embodiments of the above compounds, compounds are excludedwhere N (except where N is a heteroaryl ring atom), O, or S is bound toa carbon that is also bound to N (except where N is a heteroaryl ringatom), O, or S, except where the carbon forms a double bond with one ofthe heteroatoms, such as in an amide, carboxylic acid, and the like; orwhere N (except where N is a heteroaryl ring atom), O, C(S), C(O), orS(O)_(n) (n is 0-2) is bound to an alkene carbon of an alkenyl group orbound to an alkyne carbon of an alkynyl group; accordingly, in certainembodiments compounds which include linkages such as the following areexcluded from the present invention: —NR—CH₂—NR—, —O—CH₂—NR—,—S—CH₂—NR—, —NR—CH₂—O—, —O—CH₂—O—, —S—CH₂—O—, —NR—CH₂—S—, —O—CH₂—S—,—S—CH₂—S—, —NR—CH═CH—, —CH═CH—NR—, —NR—C≡C—, —C≡C—NR—, —O—CH═CH—,—CH═CH—O—, —O—C≡C—, —C≡C—O—, —S(O)₀₋₂—CH═CH—, —CH═CH—S(O)₀₋₂—,—S(O)₀₋₂—C≡C—, —C≡C—S(O)₀₋₂—, —C(O)—CH═CH—, CH═CH—C(O)—, —C≡C—C(O)—, or—C(O)—C≡C—, —C(S)—CH═CH—, —CH═CH—C(S)—, —C≡C—C(S)—, or —C(S)—C≡C—.

In reference to compounds herein, specification of a compound or groupof compounds includes pharmaceutically acceptable salts of suchcompound(s), prodrug(s), and all stereoisomers, unless clearly indicatedto the contrary. In reference to compounds of Formula II, unless clearlyindicated to the contrary, it is understood that such reference includescompounds of Formulae IIa, IIb, IIc, IId, IIe, IIf, IIg, IIh, III, IIj,IIk, IIm, IIn, and IIp, and all sub-embodiments thereof.

In another aspect, the invention provides methods for treating ac-kit-mediated disease or condition in an animal subject (e.g. a mammalsuch as a human, other primates, sports animals, animals of commercialinterest such as cattle, farm animals such as horses, or pets such asdogs and cats), e.g., a disease or condition characterized by abnormalc-kit activity (e.g. kinase activity). Invention methods involveadministering to the subject suffering from or at risk of ac-kit-mediated disease or condition an effective amount of a compound ofFormula II or Formula III, and all sub-embodiments thereof. In oneembodiment, the c-kit mediated disease is selected from the groupconsisting of malignancies, including, but not limited to, mast celltumors, small cell lung cancer, testicular cancer, gastrointestinalstromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma,carcinomas of the female genital tract, sarcomas of neuroectodermalorigin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasiaassociated with neurofibromatosis, acute myelocytic leukemia, acutelymphocytic leukemia, chronic myelogenous leukemia, mastocytosis,melanoma, and canine mast cell tumors, and inflammatory diseases,including, but not limited to, asthma, rheumatoid arthritis, allergicrhinitis, multiple sclerosis, inflammatory bowel syndrome, transplantrejection, and hypereosinophilia.

In a related aspect, compounds of Formula II or Formula III, and allsub-embodiments thereof, can be used in the preparation of a medicamentfor the treatment of a c-kit-mediated disease or condition selected fromthe group consisting of malignancies, including, but not limited to,mast cell tumors, small cell lung cancer, testicular cancer,gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma,neuroblastoma, carcinomas of the female genital tract, sarcomas ofneuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwanncell neoplasia associated with neurofibromatosis, acute myelocyticleukemia, acute lymphocytic leukemia, chronic myelogenous leukemia,mastocytosis, melanoma, and canine mast cell tumors, and inflammatorydiseases, including, but not limited to, asthma, rheumatoid arthritis,allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome,transplant rejection, and hypereosinophilia.

In a further aspect, the invention provides methods for treating ac-fms-mediated disease or condition in an animal subject (e.g. a mammalsuch as a human, other primates, sports animals, animals of commercialinterest such as cattle, farm animals such as horses, or pets such asdogs and cats), e.g., a disease or condition characterized by abnormalc-fms activity (e.g. kinase activity). Invention methods involveadministering to the subject suffering from or at risk of ac-fms-mediated disease or condition an effective amount of compound ofFormula II or Formula III, and all sub-embodiments thereof. In oneembodiment, the c-fms mediated disease is selected from the groupconsisting of immune disorders, including, but not limited to,rheumatoid arthritis, systemic lupus erythematosis (SLE), and transplantrejection; inflammatory diseases including, but not limited to,osteoarthritis, inflammatory bowel syndrome, ulcerative colitis, Crohn'sdisease, chronic obstructive pulmonary disease (COPD), emphysema,Kawasaki's Disease, hemophagocytic syndrome (macrophage activationsyndrome), multicentric reticulohistiocytosis, and atherosclerosis;metabolic disorders, including, but not limited to, Type I diabetes,Type II diabetes, insulin resistance, hyperglycemia, obesity, andlipolysis; disorders of bone structure, mineralization and boneformation and resorption, including, but not limited to, osteoporosis,increased risk of fracture, Paget's disease, hypercalcemia,infection-mediated osteolysis (e.g. osteomyelitis), peri-prosthetic orwear-debris-mediated osteolysis, and metastasis of cancer to bone;kidney and genitourinary diseases, including, but not limited to,endometriosis, nephritis (e.g. glomerulonephritis, interstitialnephritis, Lupus nephritis), tubular necrosis, diabetes-associated renalcomplications (e.g. diabetic nephropathy), and renal hypertrophy;disorders of the central nervous system, including, but not limited to,multiple sclerosis, stroke, Alzheimer's disease and Parkinson's disease;inflammatory and chronic pain, including, but not limited to, bone pain;and cancers, including, but not limited to, multiple myeloma, acutemyeloid leukemia (AML), chronic myeloid leukemia (CML), prostate cancer,breast cancer, ovarian cancer, melanoma, glioblastoma multiforme,metastasis of tumors to other tissues, and other chronicmyeloproliferative diseases such as myelofibrosis.

In a related aspect, compounds of Formula II or Formula III, and allsub-embodiments thereof, can be used in the preparation of a medicamentfor the treatment of a c-fms-mediated disease or condition selected fromthe group consisting of immune disorders, including, but not limited to,rheumatoid arthritis, systemic lupus erythematosis (SLE), and transplantrejection; inflammatory diseases including, but not limited to,osteoarthritis, inflammatory bowel syndrome, ulcerative colitis, Crohn'sdisease, chronic obstructive pulmonary disease (COPD), emphysema,Kawasaki's Disease, hemophagocytic syndrome (macrophage activationsyndrome), multicentric reticulohistiocytosis, and atherosclerosis;metabolic disorders, including, but not limited to, Type I diabetes,Type II diabetes, insulin resistance, hyperglycemia, obesity, andlipolysis; disorders of bone structure, mineralization and boneformation and resorption, including, but not limited to, osteoporosis,increased risk of fracture, Paget's disease, hypercalcemia,infection-mediated osteolysis (e.g. osteomyelitis), peri-prosthetic orwear-debris-mediated osteolysis, and metastasis of cancer to bone;kidney and genitourinary diseases, including, but not limited to,endometriosis, nephritis (e.g. glomerulonephritis, interstitialnephritis, Lupus nephritis), tubular necrosis, diabetes-associated renalcomplications (e.g. diabetic nephropathy), and renal hypertrophy;disorders of the central nervous system, including, but not limited to,multiple sclerosis, stroke, Alzheimer's disease and Parkinson's disease;inflammatory and chronic pain, including, but not limited to, bone pain;and cancers, including, but not limited to, multiple myeloma, acutemyeloid leukemia (AML), chronic myeloid leukemia (CML), prostate cancer,breast cancer, ovarian cancer, melanoma, glioblastoma multiforme,metastasis of tumors to other tissues, and other chronicmyeloproliferative diseases such as myelofibrosis.

In a further aspect, the invention provides methods for treating ac-fms-mediated disease or condition in an animal subject (e.g. a mammalsuch as a human, other primates, sports animals, animals of commercialinterest such as cattle, farm animals such as horses, or pets such asdogs and cats), e.g., a disease or condition characterized by abnormalc-fms activity (e.g. kinase activity). Invention methods involveadministering to the subject suffering from or at risk of ac-fms-mediated disease or condition an effective amount of compound ofFormula I, Formula Ia, Formula Ib, or Formula Ig, and allsub-embodiments thereof. In one embodiment, the c-fms mediated diseaseis selected from the group consisting of osteoarthritis, inflammatorybowel syndrome, ulcerative colitis, Crohn's disease, Kawasaki's Disease,hemophagocytic syndrome (macrophage activation syndrome), multicentricreticulohistiocytosis, Type I diabetes, Type II diabetes, obesity,Paget's disease, infection-mediated osteolysis (e.g. osteomyelitis),peri-prosthetic or wear-debris-mediated osteolysis, endometriosis,diabetic nephropathy, multiple sclerosis, stroke, Alzheimer's diseaseand Parkinson's disease, inflammatory pain, chronic pain, bone pain,prostate cancer, melanoma, glioblastoma multiforme, and metastasis oftumors to tissues other than bone, preferably the c-fms mediated diseaseis selected from the group consisting of inflammatory bowel syndrome,ulcerative colitis, Crohn's disease, Type I diabetes, Type II diabetes,Paget's disease, diabetic nephropathy, multiple sclerosis, stroke,Alzheimer's disease and Parkinson's disease, inflammatory pain, chronicpain, bone pain, prostate cancer, metastasis of tumors to tissues otherthan bone, and other chronic myeloproliferative diseases such asmyelofibrosis.

In a related aspect, compounds of Formula I, Formula Ia, Formula Ib, orFormula Ig, and all sub-embodiments thereof, can be used in thepreparation of a medicament for the treatment of a c-fms-mediateddisease or condition selected from the group consisting ofosteoarthritis, inflammatory bowel syndrome, ulcerative colitis, Crohn'sdisease, Kawasaki's Disease, hemophagocytic syndrome (macrophageactivation syndrome), multicentric reticulohistiocytosis, Type Idiabetes, Type II diabetes, obesity, Paget's disease, infection-mediatedosteolysis (e.g. osteomyelitis), peri-prosthetic or wear-debris-mediatedosteolysis, endometriosis, diabetic nephropathy, multiple sclerosis,stroke, Alzheimer's disease and Parkinson's disease, inflammatory pain,chronic pain, bone pain, prostate cancer, melanoma, glioblastomamultiforme, and metastasis of tumors to tissues other than bone,preferably the c-fms mediated disease is selected from the groupconsisting of inflammatory bowel syndrome, ulcerative colitis, Crohn'sdisease, Type I diabetes, Type II diabetes, Paget's disease, diabeticnephropathy, multiple sclerosis, stroke, Alzheimer's disease andParkinson's disease, inflammatory pain, chronic pain, bone pain,prostate cancer, metastasis of tumors to tissues other than bone, andother chronic myeloproliferative diseases such as myelofibrosis.

In a further aspect, the invention provides methods for treating, in ananimal subject (e.g. a mammal such as a human, other primates, sportsanimals, animals of commercial interest such as cattle, farm animalssuch as horses, or pets such as dogs and cats), a disease or conditionmediated by c-fms and c-kit, e.g., a disease or condition characterizedby abnormal c-fms activity and/or c-kit activity (e.g. kinase activity).Invention methods involve administering to the subject suffering from orat risk of a disease or condition mediated by c-fms and c-kit aneffective amount of compound of Formula II or Formula III, and allsub-embodiments thereof. In one embodiment, the condition mediated byc-fms and c-kit is selected from the group consisting of mast celltumors, small cell lung cancer, testicular cancer, gastrointestinalstromal tumors, glioblastoma, astrocytoma, neuroblastoma, carcinomas ofthe female genital tract, sarcomas of neuroectodermal origin, colorectalcarcinoma, carcinoma in situ, Schwann cell neoplasia associated withneurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia,chronic myelogenous leukemia, multiple myeloma, mastocytosis, melanoma,breast cancer, ovarian cancer, prostate cancer, canine mast cell tumors,metastasis of cancer to bone or other tissues, chronicmyeloproliferative diseases such as myelofibrosis, renal hypertrophy,asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis,osteoarthritis, inflammatory bowel syndrome, transplant rejection,systemic lupus erythematosis, ulcerative colitis, Crohn's disease,chronic obstructive pulmonary disease, emphysema, Kawasaki's Disease,hemophagocytic syndrome (macrophage activation syndrome), multicentricreticulohistiocytosis, atherosclerosis, Type I diabetes, Type IIdiabetes, insulin resistance, hyperglycemia, obesity, lipolysis,hypereosinophilia, osteoporosis, increased risk of fracture, Paget'sdisease, hypercalcemia, infection-mediated osteolysis (e.g.osteomyelitis), peri-prosthetic or wear-debris-mediated osteolysis,endometriosis, glomerulonephritis, interstitial nephritis, Lupusnephritis, tubular necrosis, diabetic nephropathy, stroke, Alzheimer'sdisease, Parkinson's disease, inflammatory pain, chronic pain, and bonepain.

In a related aspect, compounds of Formula II or Formula III, and allsub-embodiments thereof, can be used in the preparation of a medicamentfor the treatment of a c-fms-mediated and/or c-kit mediated disease orcondition selected from the group consisting of mast cell tumors, smallcell lung cancer, testicular cancer, gastrointestinal stromal tumors,glioblastoma, astrocytoma, neuroblastoma, carcinomas of the femalegenital tract, sarcomas of neuroectodermal origin, colorectal carcinoma,carcinoma in situ, Schwann cell neoplasia associated withneurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia,chronic myelogenous leukemia, multiple myeloma, mastocytosis, melanoma,breast cancer, ovarian cancer, prostate cancer, canine mast cell tumors,metastasis of cancer to bone or other tissues, chronicmyeloproliferative diseases such as myelofibrosis, renal hypertrophy,asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis,osteoarthritis, inflammatory bowel syndrome, transplant rejection,systemic lupus erythematosis, ulcerative colitis, Crohn's disease,chronic obstructive pulmonary disease, emphysema, Kawasaki's Disease,hemophagocytic syndrome (macrophage activation syndrome), multicentricreticulohistiocytosis, atherosclerosis, Type I diabetes, Type IIdiabetes, insulin resistance, hyperglycemia, obesity, lipolysis,hypereosinophilia, osteoporosis, increased risk of fracture, Paget'sdisease, hypercalcemia, infection-mediated osteolysis (e.g.osteomyelitis), peri-prosthetic or wear-debris-mediated osteolysis,endometriosis, glomerulonephritis, interstitial nephritis, Lupusnephritis, tubular necrosis, diabetic nephropathy, stroke, Alzheimer'sdisease, Parkinson's disease, inflammatory pain, chronic pain, and bonepain.

In particular embodiments, the compound has an IC₅₀ of less than 100 nM,less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM asdetermined in a generally accepted kinase activity assay. In certainembodiments, the selectivity of the compound is such that the compoundis at least 2-fold, 5-fold, 10-fold, or 100-fold more active on c-kitthan on Ret, PDGF, or both Ret and PDGF. In certain embodiments, theselectivity of the compound is such that the compound is at least2-fold, 5-fold, 10-fold, or 100-fold more active on c-kit than on c-fms.In certain embodiments, the selectivity of the compound is such that thecompound is at least 2-fold, 5-fold, 10-fold, or 100-fold more active onc-fms than on c-kit. In certain embodiments, the compound has incombination each pairing of activity (e.g. IC₅₀) and/or selectivity asspecified in this paragraph.

In particular embodiments, the compound has an IC₅₀ of less than 100 nM,less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM asdetermined in a generally accepted kinase activity assay for c-kit,c-fms, or both c-kit and c-fms kinase activity. In certain embodiments,the selectivity of the compound is such that the compound is at least2-fold, 5-fold, 10-fold, or 100-fold more active on c-kit, c-fins, orboth c-kit and c-fms than on Ret, PDGF, or both Ret and PDGF.

In particular embodiments, the compound has an IC₅₀ of less than 100 nM,less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM asdetermined in a generally accepted kinase activity assay for c-kit,c-fms, or both c-kit and c-fms kinase activity, and further has an IC₅₀of less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM,or less than 5 nM as determined in a generally accepted kinase activityassay for at least one of HGK, TrkA, or TrkB kinase activity.

An additional aspect of this invention relates to compositions thatinclude a therapeutically effective amount of a compound of Formula IIor Formula III and all sub-embodiments thereof and at least onepharmaceutically acceptable carrier, excipient, and/or diluent,including combinations of any two or more compounds of Formula II orFormula III. The composition can further include one or more differentpharmacologically active compounds, which can include one or morecompounds of Formula I (including Formula Ia, Ib, and Ig, and allsub-embodiments thereof), Formula II or Formula III.

In one aspect, the invention provides a method of treating a cancer byadministering to the subject an effective amount of a compositionincluding a compound of Formula II or Formula III, in combination withone or more other therapies or medical procedures effective in treatingthe cancer. Other therapies or medical procedures include suitableanticancer therapy (e.g. drug therapy, vaccine therapy, gene therapy,photodynamic therapy) or medical procedure (e.g. surgery, radiationtreatment, hyperthermia heating, bone marrow or stem cell transplant).In one aspect, the one or more suitable anticancer therapies or medicalprocedures is selected from treatment with a chemotherapeutic agent(e.g. chemotherapeutic drug), radiation treatment (e.g. x-ray, γ-ray, orelectron, proton, neutron, or a particle beam), hyperthermia heating(e.g. microwave, ultrasound, radiofrequency ablation), Vaccine therapy(e.g. AFP gene hepatocellular carcinoma vaccine, AFP adenoviral vectorvaccine, AG-858, allogeneic GM-CSF-secretion breast cancer vaccine,dendritic cell peptide vaccines), gene therapy (e.g. Ad5CMV-p53 vector,adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha),photodynamic therapy (e.g. aminolevulinic acid, motexafin lutetium),surgery, and bone marrow and stem cell transplantation.

In one aspect, the invention provides a method of treating a cancer byadministering to the subject an effective amount of a compositionincluding a compound of Formula II or Formula III, in combination withone or more suitable chemotherapeutic agents. In one aspect, the one ormore suitable chemotherapeutic agents is selected from an alkylatingagent, including, but not limited to, adozelesin, altretamine,bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil,cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine,hepsulfam, ifosfamide, improsulfan, irofulven, lomustine,mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine,streptozocin, temozolomide, thiotepa, and treosulfan; an antibiotic,including, but not limited to, bleomycin, dactinomycin, daunorubicin,doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone,neocarzinostatin, pentostatin, and plicamycin; an antimetabolite,including, but not limited to, azacitidine, capecitabine, cladribine,clofarabine, cytarabine, decitabine, floxuridine, fludarabine,5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine,methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, andtrimetrexate; an immunotherapy, including, but not limited to,alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab,pertuzumab, rituximab, tositumomab, trastuzumab, and 90 Y ibritumomabtiuxetan; a hormone or hormone antagonist, including, but not limitedto, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane,flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide,magestrol, raloxifene, tamoxifen, and toremifene; a taxane, including,but not limited to, DJ-927, docetaxel, TPI 287, paclitaxel andDHA-paclitaxel; a retinoid, including, but not limited to, alitretinoin,bexarotene, fenretinide, isotretinoin, and tretinoin; an alkaloid,including, but not limited to, etoposide, homoharringtonine, teniposide,vinblastine, vincristine, vindesine, and vinorelbine; an antiangiogenicagent, including, but not limited to, AE-941 (GW786034, Neovastat),ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; atopoisomerase inhibitor, including, but not limited to, amsacrine,edotecarin, exatecan, irinotecan (also active metabolite SN-38(7-ethyl-10-hydroxy-camptothecin)), rubitecan, topotecan, and9-aminocamptothecin; a kinase inhibitor, including, but not limited to,erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib,sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107,BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine), and vatalanib;a targeted signal transduction inhibitor including, but not limited tobortezomib, geldanamycin, and rapamycin; a biological response modifier,including, but not limited to, imiquimod, interferon-α, andinterleukin-2; and other chemotherapeutics, including, but not limitedto 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone),aminoglutethimide, asparaginase, bryostatin-1, cilengitide, E7389,ixabepilone, procarbazine, sulindac, temsirolimus, tipifamib.Preferably, the method of treating a cancer involves administering tothe subject an effective amount of a composition of Formula II, FormulaIII or Formula IV in combination with a chemotherapeutic agent selectedfrom 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin,paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, orerlotinib.

In another aspect, the invention provides a method of treating orprophylaxis of a disease or condition in a mammal, by administering tothe mammal a therapeutically effective amount of a compound of FormulaII or Formula III, a prodrug of such compound, or a pharmaceuticallyacceptable salt of such compound or prodrug. The compound can be aloneor can be part of a composition.

In a related aspect, the invention provides kits that include acomposition as described herein. In particular embodiments, thecomposition is packaged, e.g., in a vial, bottle, flask, which may befurther packaged, e.g., within a box, envelope, or bag; the compositionis approved by the U.S. Food and Drug Administration or similarregulatory agency for administration to a mammal, e.g., a human; thecomposition is approved for administration to a mammal, e.g., a human,for a c-kit- and/or c-fms-mediated disease or condition; the kit of theinvention includes written instructions on use and/or other indicationthat the composition is suitable or approved for administration to amammal, e.g., a human, for a c-kit- and/or c-fms-mediated disease orcondition; the composition is packaged in unit dose or single dose form,e.g., single dose pills, capsules, or the like.

In another aspect, the present invention also provides a method formodulating c-kit or c-fms activity by contacting c-kit or c-fms with aneffective amount of a compound of Formula II or Formula III and allsub-embodiments thereof active on c-kit and/or c-fms (such as compoundsdeveloped using methods described herein). The compound is preferablyprovided at a level sufficient to modulate the activity of the c-kit orc-fms by at least 10%, more preferably at least 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, or greater than 90%. In many embodiments, the compoundwill be at a concentration of about 1 μM, 100 μM, or 1 mM, or in a rangeof 1-100 nM, 100-500 nM, 500-1000 nM, 1-100 μM, 100-500 μM, or 500-1000μM. In particular embodiments, the contacting is carried out in vitro.

Additional aspects and embodiments will be apparent from the followingDetailed Description and from the claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein the following definitions apply:

“Halo” and “halogen” refer to all halogens, that is, chloro (Cl), fluoro(F), bromo (Br), or iodo (I).

“Hydroxyl” and “hydroxy” refer to the group —OH.

“Thiol” refers to the group —SH.

“Lower alkyl” alone or in combination means an alkane-derived radicalcontaining from 1 to 6 carbon atoms (unless specifically defined) thatincludes a straight chain alkyl or branched alkyl. The straight chain orbranched alkyl group is attached at any available point to produce astable compound. In many embodiments, a lower alkyl is a straight orbranched alkyl group containing from 1-6, 1-4, or 1-2, carbon atoms,such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like.“Optionally substituted lower alkyl” denotes lower alkyl that isindependently substituted, unless indicated otherwise, with one or more,preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached atany available atom to produce a stable compound, wherein thesubstituents are selected from the group consisting of —F, —OH, —NH₂,—NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂,—NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(a), —SR^(a), —OC(O)R^(a),—OC(S)R^(a), —C(O)R^(a), —C(S)R^(a), —C(O)OR^(a), —C(S)OR^(a),—S(O)R^(a), —S(O)₂R^(a), —C(O)NHR^(a), —C(S)NHR^(a), —C(O)NR^(a)R^(a),—C(S)NR^(a)R^(a), —S(O)₂NHR^(a), —S(O)₂NR^(a)R^(a), —C(NH)NHR^(a),—C(NH)NR^(b)R^(C), —NHC(O)R^(a), —NHC(S)R^(a), —NR^(a)C(O)R^(a),—NR^(a)C(S)R^(a), —NHS(O)₂R^(a), —NR^(a)S(O)₂R^(a), —NHC(O)NHR^(a),—NHC(S)NHR^(a), —NR^(a)C(O)NH₂, —NR^(a)C(S)NH₂, —NR^(a)C(O)NHR^(a),—NR^(a)C(S)NHR^(a), —NHC(O)NR^(a)R^(a), —NHC(S)NR^(a)R^(a),—NR^(a)C(O)NR^(a)R^(a), —NR^(a)C(S)NR^(a)R^(a), —NHS(O)₂NHR^(a),—NR^(a)S(O)₂NH₂, —NR^(a)S(O)₂NHR^(a), —NHS(O)₂NR^(a)R^(a),—NR^(a)S(O)₂NR^(a)R^(a), —NHR^(a), —NR^(a)R^(a), —R^(e), —R^(f), and—R^(g). Further, possible substitutions include subsets of thesesubstitutions, such as are indicated herein, for example, in thedescription of compounds of Formula I (including Formulae Ia, Ib, Ig andall sub-embodiments thereof), attached at any available atom to producea stable compound. For example “fluoro substituted lower alkyl” denotesa lower alkyl group substituted with one or more fluoro atoms, such asperfluoroalkyl, where preferably the lower alkyl is substituted with 1,2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it isunderstood that substitutions are attached at any available atom toproduce a stable compound, when optionally substituted alkyl is an Rgroup of a moiety such as —OR, —NHR, —C(O)NHR, and the like,substitution of the alkyl R group is such that substitution of the alkylcarbon bound to any —O—, —S—, or —N— of the moiety (except where —N— isa heteroaryl ring atom) excludes substituents that would result in any—O—, —S—, or —N— of the substituent (except where —N— is a heteroarylring atom) being bound to the alkyl carbon bound to any —O—, —S—, or —N—of the moiety.

“Lower alkylene” refers to a divalent alkane-derived radical containing1-6 carbon atoms, straight chain or branched, from which two hydrogenatoms are taken from the same carbon atom or from different carbonatoms. Examples of lower alkylene include, but are not limited to,methylene —CH₂—, ethylene —CH₂CH₂—, propylene —CH₂CH₂CH₂—, isopropylene—CH(CH₃)CH—, and the like. “Optionally substituted lower alkylene”denotes lower alkylene that is independently substituted, unlessindicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also1, 2, or 3 substituents, attached at any available atom to produce astable compound, wherein the substituents are selected from the groupconsisting of —F, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂,—C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂,—OR^(a), —SR^(a), —OC(O)R^(a), —OC(S)R^(a), —C(O)R^(a), —C(S)R^(a),—C(O)OR^(a), —C(S)OR^(a), —S(O)R^(a), —S(O)₂R^(a), —C(O)NHR^(a),—C(S)NHR^(a), —C(O)NR^(a)R^(a), —C(S)NR^(a)R^(a), —S(O)₂NHR^(a),—S(O)₂NR^(a)R^(a), —C(NH)NHR^(a), —C(NH)NR^(b)R^(c), —NHC(O)R^(a),—NHC(S)R^(a), —NR^(a)C(O)R^(a), —NR^(a)C(S)R^(a), —NHS(O)₂R^(a),—NR^(a)S(O)₂R^(a), —NHC(O)NHR^(a), NHC(S)NHR^(a), —NR^(a)C(O)NHR^(a),—NR^(a)C(O)NH₂, —NR^(a)C(S)NH₂, —NR^(a)C(S)NHR^(a), —NHC(O)NR^(a)R^(a),—NHC(S)NR^(a)R^(a), —NR^(a)C(O)NR^(a)R^(a), —NR^(a)C(S)NR^(a)R^(a),—NHS(O)₂NHR^(a), —NR^(a)S(O)₂NH₂, —NR^(a)S(O)₂NHR^(a),—NHS(O)₂NR^(a)R^(a), —NR^(a)S(O)₂NR^(a)R^(a), —NHR^(a), —NR^(a)R^(a),—R^(e), —R^(f), and —R, or two substituents on any one carbon or asubstituent on each of any two carbons in the alkylene chain may join toform a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclicheterocycloalkyl wherein the monocyclic cycloalkyl or monocyclicheterocycloalkyl are optionally substituted with one or moresubstituents selected from the group consisting of halogen, —OH, —NH₂,lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluorosubstituted lower alkoxy, lower alkylthio, fluoro substituted loweralkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.

“Lower alkenyl” alone or in combination means a straight or branchedhydrocarbon containing 2-6 carbon atoms (unless specifically defined)and at least one, preferably 1-3, more preferably 1-2, most preferablyone, carbon to carbon double bond. Carbon to carbon double bonds may beeither contained within a straight chain or branched portion. Examplesof lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl,and the like. “Substituted lower alkenyl” denotes lower alkenyl that isindependently substituted, unless indicated otherwise, with one or more,preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached atany available atom to produce a stable compound, wherein thesubstituents are selected from the group consisting of —F, —OH, —NH₂,—NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂,—NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(a), —SR^(a), —OC(O)R^(a),—OC(S)R^(a), —C(O)R^(a), —C(S)R^(a), —C(O)OR^(a), —C(S)OR^(a),—S(O)R^(a), —S(O)₂R^(a), —C(O)NHR^(a), —C(S)NHR^(a), —C(O)NR^(a)R^(a),—C(S)NR^(a)R^(a), —S(O)₂NHR^(a), —S(O)₂NR^(a)R^(a), —C(NH)NHR^(a),—C(NH)NR^(b)R^(a), —NHC(O)R^(a), —NHC(S)R^(a), —NR^(a)C(O)R^(a),—NR^(a)C(S)R^(a), —NHS(O)₂R^(a), —NR^(a)S(O)₂R^(a), —NHC(O)NHR^(a),—NHC(S)NHR^(a), —NR^(a)C(O)NH₂, —NR^(a)C(S)NH₂, —NR^(a)C(O)NHR^(a),—NR^(a)C(S)NHR^(a), —NHC(O)NR^(a)R^(a), —NHC(S)NR^(a)R^(a),—NR^(a)C(O)NR^(a)R^(a), —NR^(a)C(S)NR^(a)R^(a), —NHS(O)₂NHR^(a),—NR^(a)S(O)₂NH₂, —NR^(a)S(O)₂NHR^(a), —NHS(O)₂NR^(a)R^(a),—NR^(a)S(O)₂NR^(a)R^(a), —NHR^(a), —NR^(a)R^(a), —R^(d), —R^(f), and—R^(g). Further, possible substitutions include subsets of thesesubstitutions, such as are indicated herein, for example, in thedescription of compounds of Formula I (including Formulae Ia, Ib, Ig andall sub-embodiments thereof), attached at any available atom to producea stable compound. For example “fluoro substituted lower alkenyl”denotes a lower alkenyl group substituted with one or more fluoro atoms,where preferably the lower alkenyl is substituted with 1, 2, 3, 4 or 5fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood thatsubstitutions are attached at any available atom to produce a stablecompound, substitution of alkenyl groups are such that —F, —C(O)—,—C(S)—, —C(NH)—, —S(O)—, —S(O)₂—, —O—, —S—, or —N-(except where —N— is aheteroaryl ring atom), are not bound to an alkene carbon thereof.Further, where alkenyl is a substituent of another moiety or an R groupof a moiety such as —OR, —NHR, —C(O)R, and the like, substitution of themoiety is such that any —C(O)—, —C(S)—, —S(O)—, —S(O)₂—, —O—, —S—, or—N-thereof (except where —N— is a heteroaryl ring atom) are not bound toan alkene carbon of the alkenyl substituent or R group. Further, wherealkenyl is a substituent of another moiety or an R group of a moietysuch as —OR, —NHR, —C(O)NHR, and the like, substitution of the alkenyl Rgroup is such that substitution of the alkenyl carbon bound to any —O—,—S—, or —N— of the moiety (except where —N— is a heteroaryl ring atom)excludes substituents that would result in any —O—, —S—, or —N— of thesubstituent (except where —N— is a heteroaryl ring atom) being bound tothe alkenyl carbon bound to any —O—, —S—, or —N— of the moiety. An“alkenyl carbon” refers to any carbon within an alkenyl group, whethersaturated or part of the carbon to carbon double bond. An “alkenecarbon” refers to a carbon within an alkenyl group that is part of acarbon to carbon double bond.

“Lower alkynyl” alone or in combination means a straight or branchedhydrocarbon containing 2-6 carbon atoms (unless specifically defined)containing at least one, preferably one, carbon to carbon triple bond.Examples of alkynyl groups include ethynyl, propynyl, butynyl, and thelike. “Substituted lower alkynyl” denotes lower alkynyl that isindependently substituted, unless indicated otherwise, with one or more,preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached atany available atom to produce a stable compound, wherein thesubstituents are selected from the group consisting of —F, —OH, —NH₂,—NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂,—NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(a), —SR^(a), —OC(O)R^(a),—OC(S)R^(a), —C(O)R^(a), —C(S)R^(a), —C(O)OR^(a), —C(S)OR^(a),—S(O)R^(a), —S(O)₂R^(a), —C(O)NHR^(a), —C(S)NHR^(a), —C(O)NR^(a)R^(a),—C(S)NR^(a)R^(a), —S(O)₂NHR^(a), —S(O)₂NR^(a)R^(a), —C(NH)NHR^(a),—C(NH)NR^(b)R^(e), —NHC(O)R^(a), —NHC(S)R^(a), —NR^(a)C(O)R^(a),—NR^(a)C(S)R^(a), —NHS(O)₂R^(a), —NR^(a)S(O)₂R^(a), —NHC(O)NHR^(a),—NHC(S)NHR^(a), —NR^(a)C(O)NH₂, —NR^(a)C(S)NH₂, —NR^(a)C(O)NHR^(a),—NR^(a)C(S)NHR^(a), —NHC(O)NR^(a)R^(a), —NHC(S)NR^(a)R^(a),—NR^(a)C(O)NR^(a)R^(a), —NR^(a)C(S)NR^(a)R^(a), —NHS(O)₂NHR^(a),—NR^(a)S(O)₂NH₂, —NR^(a)S(O)₂NHR^(a), —NHS(O)₂NR^(a)R^(a),—NR^(a)S(O)₂NR^(a)R^(a), —NHR^(a), —NR^(a)R^(a), —R^(d), —R^(e), and—R^(g). Further, possible substitutions include subsets of thesesubstitutions, such as are indicated herein, for example, in thedescription of compounds of Formula I (including Formulae Ia, Ib, Ig andall sub-embodiments thereof), attached at any available atom to producea stable compound. For example “fluoro substituted lower alkynyl”denotes a lower alkynyl group substituted with one or more fluoro atoms,where preferably the lower alkynyl is substituted with 1, 2, 3, 4 orfluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood thatsubstitutions are attached at any available atom to produce a stablecompound, substitution of alkynyl groups are such that —F, —C(O)—,—C(S)—, —C(NH)—, —S(O)—, —S(O)₂—, —O—, —S—, or —N-(except where —N— is aheteroaryl ring atom), are not bound to an alkyne carbon thereof.Further, where alkynyl is a substituent of another moiety or an R groupof a moiety such as —OR, —NHR, —C(O)R, and the like, substitution of themoiety is such that any —C(O)—, —C(S)—, —S(O)—, —S(O)₂—, —O—, —S—, or—N— thereof (except where —N— is a heteroaryl ring atom) are not boundto an alkyne carbon of the alkynyl substituent or R group. Further,where alkynyl is a substituent of another moiety or an R group of amoiety such as —OR, —NHR, —C(O)NHR, and the like, substitution of thealkynyl R group is such that substitution of the alkynyl carbon bound toany —O—, —S—, or —N— of the moiety (except where —N— is a heteroarylring atom) excludes substituents that would result in any —O—, —S—, or—N— of the substituent (except where —N— is a heteroaryl ring atom)being bound to the alkynyl carbon bound to any —O—, —S—, or —N— of themoiety. An “alkynyl carbon” refers to any carbon within an alkynylgroup, whether saturated or part of the carbon to carbon triple bond. An“alkyne carbon” refers to a carbon within an alkynyl group that is partof a carbon to carbon triple bond.

“Cycloalkyl” refers to saturated or unsaturated, non-aromaticmonocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8,more preferably 3-6, ring members per ring, such as cyclopropyl,cyclopentyl, cyclohexyl, adamantyl, and the like. “Cycloalkylene” is adivalent cycloalkyl. A “substituted cycloalkyl” is a cycloalkyl that isindependently substituted, unless indicated otherwise, with one or more,preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached atany available atom to produce a stable compound, wherein thesubstituents are selected from the group consisting of halogen, —OH,—NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂,—NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(a), —SR^(a),—OC(O)R^(a), —OC(S)R^(a), —C(O)R^(a), —C(S)R^(a), —C(O)OR^(a),—C(S)OR^(a), —S(O)R^(a), —S(O)₂R^(a), —C(O)NHR^(a), —C(S)NHR^(a),—C(O)NR^(a)R^(a), —C(S)NR^(a)R^(a), —S(O)₂NHR^(a), —S(O)₂NR^(a)R^(a),—C(NH)NHR^(a), —C(NH)NR^(b)R^(e), —NHC(O)R^(a), —NHC(S)R^(a),—NR^(a)C(O)R^(a), —NR^(a)C(S)R^(a), —NHS(O)₂R^(a), —NR^(a)S(O)₂R^(a),—NHC(O)NHR^(a), —NHC(S)NHR^(a), —NR^(a)C(O)NH₂, —NR^(a)C(S)NH₂,—NR^(a)C(O)NHR^(a), —NR^(a)C(S)NHR^(a), —NHC(O)NR^(a)R^(a),—NHC(S)NR^(a)R^(a), —NR^(a)C(O)NR^(a)R^(a), —NR^(a)C(S)NR^(a)R^(a),—NHS(O)₂NHR^(a), —NR^(a)S(O)₂NH₂, —NR^(a)S(O)₂NHR^(a),—NHS(O)₂NR^(a)R^(a), —NR^(a)S(O)₂NR^(a)R^(a), —NHR^(a), —NR^(a)R^(a),—R^(d), —R^(e), —R^(f), and —R^(g). “Substituted cycloalkylene” is adivalent substituted cycloalkyl.

“Heterocycloalkyl” refers to a saturated or unsaturated non-aromaticcycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbonatoms in the ring are replaced by heteroatoms of O, S or N, and areoptionally fused with benzo or heteroaryl of 5-6 ring members.Heterocycloalkyl is also intended to include oxidized S or N, such assulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen.Heterocycloalkyl is also intended to include compounds in which one ofthe ring carbons is oxo substituted, i.e. the ring carbon is a carbonylgroup, such as lactones and lactams. The point of attachment of theheterocycloalkyl ring is at a carbon or nitrogen atom such that a stablering is retained. Examples of heterocycloalkyl groups include, but arenot limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl,piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl,and dihydroindolyl. “Heterocycloalkylene” is a divalentheterocycloalkyl. A “substituted heterocycloalkyl” is a heterocycloalkylthat is independently substituted, unless indicated otherwise, with oneor more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents,attached at any available atom to produce a stable compound, wherein thesubstituents are selected from the group consisting of halogen, —OH,—NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂,—NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(a), —SR^(a),—OC(O)R^(a), —OC(S)R^(a), —C(O)R^(a), —C(S)R^(a), —C(O)OR^(a),—C(S)OR^(a), —S(O)R^(a), —S(O)₂R^(a), —C(O)NHR^(a), —C(S)NHR^(a),—C(O)NR^(a)R^(a), —C(S)NR^(a)R^(a), —S(O)₂NHR^(a), —S(O)₂NR^(a)R^(a),—C(NH)NHR^(a), —C(NH)NR^(b)R^(c), —NHC(O)R^(a), —NHC(S)R^(a),—NR^(a)C(O)R^(a), —NR^(a)C(S)R^(a), —NHS(O)₂R^(a), —NR^(a)S(O)₂R^(a),—NHC(O)NHR^(a), —NHC(S)NHR^(a), —NR^(a)C(O)NH₂, —NR^(a)C(S)NH₂,—NR^(a)C(O)NHR^(a), —NR^(a)C(S)NHR^(a), —NHC(O)NR^(a)R^(a),—NHC(S)NR^(a)R^(a), —NR^(a)C(O)NR^(a)R^(a), —NR^(a)C(S)NR^(a)R^(a),—NHS(O)₂NHR^(a), —NR^(a)S(O)₂NH₂, —NR^(a)S(O)₂NHR^(a),—NHS(O)₂NR^(a)R^(a), —NR^(a)S(O)₂NR^(a)R^(a), —NHR^(a), —NR^(a)R^(a),—R^(d), —R^(e), —R^(f), and —R^(g). “Substituted heterocycloalkylene” isa divalent substituted heterocycloalkyl.

“Aryl” alone or in combination refers to a monocyclic or bicyclic ringsystem containing aromatic hydrocarbons such as phenyl or naphthyl,which may be optionally fused with a cycloalkyl of preferably 5-7, morepreferably 5-6, ring members. “Arylene” is a divalent aryl. A“substituted aryl” is an aryl that is independently substituted, unlessindicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also1, 2, or 3 substituents, attached at any available atom to produce astable compound, wherein the substituents are selected from the groupconsisting of halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂,—C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂,—OR^(a), —SR^(a), —OC(O)R^(a), —OC(S)R^(a), —C(O)R^(a), —C(S)R^(a),—C(O)OR^(a), —C(S)OR^(a), —S(O)R^(a), —S(O)₂R^(a), —C(O)NHR^(a),—C(S)NHR^(a), —C(O)NR^(a)R^(a), —C(S)NR^(a)R^(a), —S(O)₂NHR^(a),—S(O)₂NR^(a)R^(a), C(NH)NHR^(a), —C(NH)NR^(b)R^(a), —NHC(O)R^(a),—NHC(S)R^(a), —NR^(a)C(O)R^(a), —NR^(a)C(S)R^(a), —NHS(O)₂R^(a),—NR^(a)S(O)₂R^(a), —NHC(O)NHR^(a), —NHC(S)NHR^(a), —NR^(a)C(O)NH₂,—NR^(a)C(S)NH₂, —NR^(a)C(O)NHR^(a), —NR^(a)C(S)NHR^(a),—NHC(O)NR^(a)R^(a), —NHC(S)NR^(a)R^(a), —NR^(a)C(O)NR^(a)R^(a),—NR^(a)C(S)NR^(a)R^(a), —NHS(O)₂NHR^(a), —NR^(a)S(O)₂NH₂,—NR^(a)S(O)₂NHR^(a), —NHS(O)₂NR^(a)R^(a), —NR^(a)S(O)₂NR^(a)R^(a),—NHR^(a), —NR^(a)R^(a), —R^(d), —R^(e), —R^(f), and —R^(g). A“substituted arylene” is a divalent substituted aryl.

“Heteroaryl” alone or in combination refers to a monocyclic aromaticring structure containing 5 or 6 ring atoms, or a bicyclic aromaticgroup having 8 to 10 atoms, containing one or more, preferably 1-4, morepreferably 1-3, even more preferably 1-2, heteroatoms independentlyselected from the group consisting of O, S, and N. Heteroaryl is alsointended to include oxidized S or N, such as sulfinyl, sulfonyl andN-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is thepoint of attachment of the heteroaryl ring structure such that a stablecompound is produced. Examples of heteroaryl groups include, but are notlimited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl,benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl,pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl,oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl,furanyl, benzofuryl, and indolyl. “Nitrogen containing heteroaryl”refers to heteroaryl wherein any heteroatoms are N. “Heteroarylene” is adivalent heteroaryl. A “substituted heteroaryl” is a heteroaryl that isindependently substituted, unless indicated otherwise, with one or more,preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached atany available atom to produce a stable compound, wherein thesubstituents are selected from the group consisting of halogen, —OH,—NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂,—NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(a), —SR^(a),—OC(O)R^(a), —OC(S)R^(a), —C(O)R^(a), —C(S)R^(a), —C(O)OR^(a),—C(S)OR^(a), —S(O)R^(a), —S(O)₂R^(a), —C(O)NHR^(a), —C(S)NHR^(a),—C(O)NR^(a)R^(a), —C(S)NR^(a)R^(a), S(O)₂NHR^(a), —S(O)₂NR^(a)R^(a),—C(NH)NHR^(a), —C(NH)NR^(b)R^(e), —NHC(O)R^(a), —NHC(S)R^(a),—NR^(a)C(O)R^(a), —NR^(a)C(S)R^(a), —NHS(O)₂R^(a), —NR^(a)S(O)₂R^(a),—NHC(O)NHR^(a), —NHC(S)NHR^(a), —NR^(a)C(O)NH₂, —NR^(a)C(S)NH₂,—NR^(a)C(O)NHR^(a), —NR^(a)C(S)NHR^(a), —NHC(O)NR^(a)R^(a),—NHC(S)NR^(a)R^(a), —NR^(a)C(O)NR^(a)R^(a), —NR^(a)C(S)NR^(a)R^(a),—NHS(O)₂NHR^(a), —NR^(a)S(O)₂NH₂, —NR^(a)S(O)₂NHR^(a),—NHS(O)₂NR^(a)R^(a), —NR^(a)S(O)₂NR^(a)R^(a), —NHR^(a), —NR^(a)R^(a),—R^(d), —R^(e), —R^(f), and —R^(g). “Substituted heteroarylene” is adivalent substituted heteroaryl.

The variables R^(a), R^(b), R^(c), —R^(d), —R^(e), —R^(f) and —R^(g) asused in the description of optional substituents for alkyl, alkylene,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl aredefined as follows:

each R^(a), R^(b), and R^(e) are independently selected from the groupconsisting of —R^(d), —R^(e), —R^(f), and —R^(g), or R^(b) and R^(c)combine with the nitrogen to which they are attached to form a 5-7membered heterocycloalkyl or a 5 or 7 membered nitrogen containingheteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 memberednitrogen containing heteroaryl are optionally substituted with one ormore, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selectedfrom the group consisting of halogen, —NO₂, —CN, —OH, —NH₂, —OR^(u),—SR^(u), —NHR^(u), —NR^(u)R^(u), —R^(x), and —R^(y);each —R^(d) is independently lower alkyl, wherein lower alkyl isoptionally substituted with one or more, preferably 1, 2, 3, 4 or 5,also 1, 2 or 3 substituents selected from the group consisting offluoro, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂,—S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(k),—SR^(k), —OC(O)R^(k), —OC(S)R^(k), —C(O)R^(k), —C(S)R^(k), —C(O)OR^(k),—C(S)OR^(k), —S(O)R^(k), —S(O)₂R^(k), —C(O)NHR^(k), —C(S)NHR^(k),—C(O)NR^(k)R^(k), —C(S)NR^(k)R^(k), —S(O)₂NHR^(k), —S(O)₂NR^(k)R^(k),—C(NH)NHR^(k), —C(NH)NR^(m)R^(n), —NHC(O)R^(k), —NHC(S)R^(k),—NR^(k)C(O)R^(k), —NR^(k)C(S)R^(k), —NHS(O)₂R^(k), —NR^(k)S(O)₂R^(k),—NHC(O)NHR^(k), —NHC(S)NHR^(k), —NR^(k)C(O)NH₂, —NR^(k)C(S)NH₂,—NR^(k)C(O)NHR^(k), —NR^(k)C(S)NHR^(k), —NHC(O)NR^(k)R^(k),—NHC(S)NR^(k)R^(k), —NR^(k)C(O)NR^(k)R^(k), —NR^(k)C(S)NR^(k)R^(k),—NHS(O)₂NHR^(k), —NR^(k)S(O)₂NH₂, —NR^(k)S(O)₂NHR^(k),—NHS(O)₂NR^(k)R^(k), NR^(k)S(O)₂NR^(k)R^(k), —NHR^(k), —NR^(k)R^(k),—R^(i), and —R^(j);each —R^(e) is independently lower alkenyl, wherein lower alkenyl isoptionally substituted with one or more, preferably 1, 2, 3, 4 or 5,also 1, 2 or 3 substituents selected from the group consisting offluoro, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂,—S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(k),—SR^(k), —OC(O)R^(k), —OC(S)R^(k), —C(O)R^(k), —C(S)R^(k), —C(O)OR^(k),—C(S)OR^(k), —S(O)R^(k), —S(O)₂R^(k), —C(O)NHR^(k), —C(S)NHR^(k),—C(O)NR^(k)R^(k), —C(S)NR^(k)R^(k), —S(O)₂NHR^(k), —S(O)₂NR^(k)R^(k),—C(NH)NHR^(k), —C(NH)NR^(m)R^(n), —NHC(O)R^(k), —NHC(S)R^(k),—NR^(k)C(O)R^(k), —NR^(k)C(S)R^(k), —NHS(O)₂R^(k), —NR^(k)S(O)₂R^(k),—NHC(O)NHR^(k), —NHC(S)NHR^(k), —NR^(k)C(O)NH₂, —NR^(k)C(S)NH₂,—NR^(k)C(O)NHR^(k), —NR^(k)C(S)NHR^(k), —NHC(O)NR^(k)R^(k),—NHC(S)NR^(k)R^(k), —NR^(k)C(O)NR^(k)R^(k), —NR^(k)C(S)NR^(k)R^(k),—NHS(O)₂NHR^(k), —NR^(k)S(O)₂NH₂, —NR^(k)S(O)₂NHR^(k),—NHS(O)₂NR^(k)R^(k), —NR^(k)S(O)₂NR^(k)R^(k), —NHR^(k), —NR^(k)R^(k),—R^(h), and —R^(j);each —R^(f) is independently lower alkynyl, wherein lower alkynyl isoptionally substituted with one or more, preferably 1, 2, 3, 4 or 5,also 1, 2 or 3 substituents selected from the group consisting offluoro, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂,—S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(k),—SR^(k), —OC(O)R^(k), —OC(S)R^(k), —C(O)R^(k), —C(S)R^(k), —C(O)OR^(k),—C(S)OR^(k), —S(O)R^(k), —S(O)₂R^(k), —C(O)NHR^(k), —C(S)NHR^(k),—C(O)NR^(k)R^(k), —C(S)NR^(k)R^(k), —S(O)₂NHR^(k), —S(O)₂NR^(k)R^(k),—C(NH)NHR^(k), —C(NH)NR^(m)R^(n), —NHC(O)R^(k), —NHC(S)R^(k),—NR^(k)C(O)R^(k), —NR^(k)C(S)R^(k), —NHS(O)₂R^(k), —NR^(k)S(O)₂R^(k),—NHC(O)NHR^(k), —NHC(S)NHR^(k), —NR^(k)C(O)NH₂, —NR^(k)C(S)NH₂,—NR^(k)C(O)NHR^(k), —NR^(k)C(S)NHR^(k), —NHC(O)NR^(k)R^(k),—NHC(S)NR^(k)R^(k), —NR^(k)C(O)NR^(k)R^(k), —NR^(k)C(S)NR^(k)R^(k),—NHS(O)₂NHR^(k), —NR^(k)S(O)₂NH₂, —NR^(k)S(O)₂NHR^(k),—NHS(O)₂NR^(k)R^(k), NR^(k)S(O)₂NR^(k)R^(k), —NHR^(k), —NR^(k)R^(k),—R^(h), and —R^(j);each —R^(g) is independently selected from the group consisting ofcycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl, and heteroaryl are optionally substituted withone or more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituentsselected from the group consisting of halogen, —OH, —NH₂, —NO₂, —CN,—C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR^(k), —SR^(k), —OC(O)R^(k), —OC(S)R^(k),—C(O)R^(k), —C(S)R^(k), —C(O)OR^(k), —C(S)OR^(k), —S(O)R^(k),—S(O)₂R^(k), —C(O)NHR^(k), —C(S)NHR^(k), —C(O)NR^(k)R^(k),—C(S)NR^(k)R^(k), —S(O)₂NHR^(k), —S(O)₂NR^(k)R^(k), —C(NH)NHR^(k),—C(NH)NR^(m)R^(n), —NHC(O)R^(k), —NHC(S)R^(k), —NR^(k)C(O)R^(k),—NR^(k)C(S)R^(k), —NHS(O)₂R^(k), —NR^(k)S(O)₂R^(k), —NHC(O)NHR^(k),—NHC(S)NHR^(k), —NR^(k)C(O)NH₂, —NR^(k)C(S)NH₂, —NR^(k)C(O)NHR^(k),—NR^(k)C(S)NHR^(k), —NHC(O)NR^(k)R^(k), —NHC(S)NR^(k)R^(k),—NR^(k)C(O)NR^(k)R^(k), —NR^(k)C(S)NR^(k)R^(k), —NHS(O)₂NHR^(k),—NR^(k)S(O)₂NH₂, —NR^(k)S(O)₂NHR^(k), —NHS(O)₂NR^(k)R^(k),—NR^(k)S(O)₂NR^(k)R^(k), —NHR^(k), —NR^(k)R^(k), —R^(h), —R^(i), and —R;

-   -   wherein R^(k), R^(m), and R^(n) at each occurrence are        independently selected from the group consisting of —R^(h),        —R^(i), and —R^(j), or R^(m) and R^(n) combine with the nitrogen        to which they are attached form a 5-7 membered heterocycloalkyl        or a 5 or 7 membered nitrogen containing heteroaryl, wherein the        5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen        containing heteroaryl are optionally substituted with one or        more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents        selected from the group consisting of halogen, —NO₂, —CN, —OH,        —NH₂, OR^(u), —SR^(u), —NHR^(u), —NR^(u)R^(u), —R^(x), and        —R^(y);    -   wherein each —R^(h) is independently lower alkyl optionally        substituted with one or more, preferably 1, 2, 3, 4 or 5, also        1, 2, or 3 substituents selected from the group consisting of        fluoro, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂,        —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂,        —C(NH)NH₂, —OR^(r), —SR^(r), —OC(O)R^(r), —OC(S)R^(r),        —C(O)R^(r), —C(S)R^(r), —C(O)OR^(r), —C(S)OR^(r), —S(O)R^(r),        —S(O)₂R^(r), —C(O)NHR^(r), —C(S)NHR^(r), —C(O)NR^(r)R^(r),        —C(S)NR^(r)R^(r), —S(O)₂NHR^(r), —S(O)₂NR^(r)R^(r),        —C(NH)NHR^(r), —C(NH)NR^(r)R^(t), —NHC(O)R^(r), —NHC(S)R^(r),        —NR^(r)C(O)R^(r), —NR^(r)C(S)R^(r), —NHS(O)₂R^(r),        —NR^(r)S(O)₂R^(r), —NHC(O)NHR^(r), —NHC(S)NHR^(r),        —NR^(r)C(O)NH₂, —NR^(r)C(S)NH₂, —NR^(r)C(O)NHR^(r),        —NR^(r)C(S)NHR^(r), —NHC(O)NR^(r)R^(r), —NHC(S)NR^(r)R^(r),        —NR^(r)C(O)NR^(r)R^(r), NR^(r)C(S)NR^(r)R^(r), —NHS(O)₂NHR^(r),        —NR^(r)S(O)₂NH₂, —NR^(r)S(O)₂NHR^(r), —NHS(O)₂NR^(r)R^(r),        —NR^(r)S(O)₂NR^(r)R^(r), —NHR^(r), —NR^(r)R^(r), —R^(i), and —R;    -   wherein each —R^(i) is independently selected from the group        consisting of lower alkenyl and lower alkynyl, wherein lower        alkenyl or lower alkynyl are optionally substituted with one or        more, preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents        selected from the group consisting of fluoro, —OH, —NH₂, —NO₂,        —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂,        —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(r),        —SR^(r), —OC(O)R^(r), —OC(S)R^(r), —C(O)R^(r), —C(S)R^(r),        —C(O)OR^(r), —C(S)OR^(r), —S(O)R^(r), —S(O)₂R^(r), C(O)NHR^(r),        —C(S)NHR^(r), —C(O)NR^(r)R^(r), —C(S)NR^(r)R^(r), —S(O)₂NHR^(r),        —S(O)₂NR^(r)R^(r), —C(NH)NHR^(r), —C(NH)NR^(r)R^(t),        —NHC(O)R^(r), —NHC(S)R^(r), —NR^(r)C(O)R^(r), —NR^(r)C(S)R^(r),        —NHS(O)₂R^(r), —NR^(r)S(O)₂R^(r), —NHC(O)NHR^(r),        —NHC(S)NHR^(r), —NR^(r)C(O)NH₂, —NR^(r)C(S)NH₂,        —NR^(r)C(O)NHR^(r), —NR^(r)C(S)NHR^(r), —NHC(O)NR^(r)R^(r),        —NHC(S)NR^(r)R^(r), —NR^(r)C(O)NR^(r)R^(r),        —NR^(r)C(S)NR^(r)R^(r), —NHS(O)₂NHR^(r), —NR^(r)S(O)₂NH₂,        —NR^(r)S(O)₂NHR^(r), —NHS(O)₂NR^(r)R^(r),        —NR^(r)S(O)₂NR^(r)R^(r), —NHR^(r), —NR^(r)R^(r), and —RJ;    -   wherein each —R^(j) is independently selected from the group        consisting of cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl are optionally substituted with one or more,        preferably 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected        from the group consisting of halogen, —OH, —NH₂, —NO₂, —CN,        —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂,        —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(r), —SR^(r),        —OC(O)R^(r), —OC(S)R^(r), —C(O)R^(r), —C(S)R^(r), —C(O)OR^(r),        —C(S)OR^(r), —S(O)R^(r), —S(O)₂R^(r), —C(O)NHR^(r),        —C(S)NHR^(r), —C(O)NR^(r)R^(r), —C(S)NR^(r)R^(r), —S(O)₂NHR^(r),        —S(O)₂NR^(r)R^(r), —C(NH)NHR^(r), —C(NH)NR^(r)R^(t),        —NHC(O)R^(r), —NHC(S)R^(r), —NR^(r)C(O)R^(r), —NR^(r)C(S)R^(r),        —NHS(O)₂R^(r), —NR^(r)S(O)₂R^(r), —NHC(O)NHR^(r),        —NHC(S)NHR^(r), —NR^(r)C(O)NH₂, —NR^(r)C(S)NH₂,        —NR^(r)C(O)NHR^(r), —NR^(r)C(S)NHR^(r), —NHC(O)NR^(r)R^(r),        —NHC(S)NR^(r)R^(r), —NR^(r)C(O)NR^(r)R^(r),        —NR^(r)C(S)NR^(r)R^(r), —NHS(O)₂NHR^(r), —NR^(r)S(O)₂NH₂,        —NR^(r)S(O)₂NHR^(r), —NHS(O)₂NR^(r)R^(r),        —NR^(r)S(O)₂NR^(r)R^(r), —NHR^(r), —NR^(r)R^(r),        cycloalkylamino, and —R^(x);        -   wherein each R^(r), R^(s), and R^(t) at each occurrence are            independently selected from the group consisting of lower            alkyl, C₃₋₆alkenyl, C₃₋₆alkynyl, cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl            is optionally substituted with one or more, preferably 1, 2,            3, 4 or 5, also 1, 2, or 3 substituents selected from the            group consisting of —R, fluoro, —OH, —NH₂, lower alkoxy,            fluoro substituted lower alkoxy, lower alkylthio, fluoro            substituted lower alkylthio, mono-alkylamino, di-alkylamino,            and cycloalkylamino, provided that any substitution of the            lower alkyl carbon bound to any —O—, —S—, or —N—, of            —OR^(r), —SR^(r), —C(O)OR^(r), —C(S)OR^(r), —C(O)NHR^(r),            —C(S)NHR^(r), —C(O)NR^(r)R^(r), —C(S)NR^(r)R^(r),            —S(O)₂NHR^(r), —S(O)₂NR^(r)R^(r), —C(NH)NHR^(r),            —NR^(r)C(O)R^(r), —NR^(r)C(S)R^(r), —NR^(r)S(O)₂R^(r),            —NHC(O)NHR^(r), —NHC(S)NHR^(r), —NR^(r)C(O)NH₂,            —NR^(r)C(S)NH₂, —NR^(r)C(O)NHR^(r), —NR^(r)C(S)NHR^(r),            —NHC(O)NR^(r)R^(r), —NHC(S)NR^(r)R^(r),            —NR^(r)C(O)NR^(r)R^(r), —NR^(r)C(S)NR^(r)R^(r),            —NHS(O)₂NHR^(r), —NR^(r)S(O)₂NH₂, —NR^(r)S(O)₂NHR^(r),            —NHS(O)₂NR^(r)R^(r), —NR^(r)S(O)₂NR^(r)R^(r), —NHR^(r), or            —NR^(r)R^(r) is selected from the group consisting of fluoro            and —R^(y), and wherein C₃₋₆alkenyl or C₃₋₆alkynyl are            optionally substituted with one or more, preferably 1, 2, 3,            4 or 5, also 1, 2, or 3 substituents selected from the group            consisting of —R^(y), fluoro, lower alkyl, fluoro            substituted lower alkyl, lower alkoxy, fluoro substituted            lower alkoxy, lower alkylthio, fluoro substituted lower            alkylthio, mono-alkylamino, di-alkylamino, and            cycloalkylamino, provided that any substitution of the            C₃₋₆alkenyl or C₃₋₆alkynyl carbon bound to any —O—, —S—, or            —N—, of —OR^(r), —SR^(r), —C(O)OR^(r), —C(S)OR^(r),            —C(O)NHR^(r), —C(S)NHR^(r), —C(O)NR^(r)R^(r),            —C(S)NR^(r)R^(r), —S(O)₂NHR^(r), —S(O)₂NR^(r)R^(r),            —C(NH)NHR^(r), —NR^(r)C(O)R^(r), —NR^(r)C(S)R^(r),            —NR^(r)S(O)₂R^(r), —NHC(O)NHR^(r), —NHC(S)NHR^(r),            —NR^(r)C(O)NH₂, —NR^(r)C(S)NH₂, —NR^(r)C(O)NHR^(r),            —NR^(r)C(S)NHR^(r), —NHC(O)NR^(r)R^(r), —NHC(S)NR^(r)R^(r),            —NR^(r)C(O)NR^(r)R^(r), —NR^(r)C(S)NR^(r)R^(r),            —NHS(O)₂NHR^(r), —NR^(r)S(O)₂NH₂, —NR^(r)S(O)₂NHR^(r),            —NHS(O)₂NR^(r)R^(r), —NR^(r)S(O)₂NR^(r)R^(r), —NHR^(r), or            —NR^(r)R^(r) is selected from the group consisting of            fluoro, lower alkyl, fluoro substituted lower alkyl, or            —R^(y), and wherein cycloalkyl, heterocycloalkyl, aryl, and            heteroaryl are optionally substituted with one or more,            preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents            selected from the group consisting of halogen, —OH, —NH₂,            —NO₂, —CN, lower alkyl, fluoro substituted lower alkyl,            lower alkoxy, fluoro substituted lower alkoxy, lower            alkylthio, fluoro substituted lower alkylthio, mono-alkyl            amino, di-alkyl amino, and cycloalkylamino, or R^(s) and            R^(t) combine with the nitrogen to which they are attached            form a 5-7 membered heterocycloalkyl or a 5 or 7 membered            nitrogen containing heteroaryl, wherein the 5-7 membered            heterocycloalkyl or 5 or 7 membered nitrogen containing            heteroaryl are optionally substituted with one or more,            preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents            selected from the group consisting of halogen, —NO₂, —CN,            —OH, —NH₂, OR^(u), —SR^(u), —NHR^(u), —NR^(u)R^(u), —R^(x),            and —R^(y);        -   wherein each R^(u) is independently selected from the group            consisting of lower alkyl, C₃₋₆alkenyl, C₃₋₆alkynyl,            cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein            lower alkyl is optionally substituted with one or more,            preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents            selected from the group consisting of —R^(y), fluoro, —OH,            —NH₂, lower alkoxy, fluoro substituted lower alkoxy, lower            alkylthio, fluoro substituted lower alkylthio,            mono-alkylamino, di-alkylamino, and cycloalkylamino,            provided that any substitution of the lower alkyl carbon            bound to the —O— of —OR^(u), —S— of —SR^(u), or —N— of            —NHR^(u) is fluoro or —R^(y), and wherein C₃₋₆alkenyl or            C₃₋₆alkynyl are optionally substituted with one or more,            preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents            selected from the group consisting of —R^(y), fluoro, —OH,            —NH₂, lower alkyl, fluoro substituted lower alkyl, lower            alkoxy, fluoro substituted lower alkoxy, lower alkylthio,            fluoro substituted lower alkylthio, mono-alkylamino,            di-alkylamino, and cycloalkylamino, provided that any            substitution of the C₃₋₆alkenyl or C₃₋₆alkynyl carbon bound            to the —O— of —OR^(u), —S— of —SR^(u), or —N— of —NHR^(u) is            fluoro, lower alkyl, fluoro substituted lower alkyl, or            —R^(y), and wherein cycloalkyl, heterocycloalkyl, aryl, and            heteroaryl are optionally substituted with one or more,            preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents            selected from the group consisting of halogen, —OH, —NH₂,            —NO₂, —CN, lower alkyl, fluoro substituted lower alkyl,            lower alkoxy, fluoro substituted lower alkoxy, lower            alkylthio, fluoro substituted lower alkylthio, mono-alkyl            amino, di-alkyl amino, and cycloalkylamino;        -   wherein each —R^(x) is selected from the group consisting of            lower alkyl, lower alkenyl and lower alkynyl, wherein lower            alkyl is optionally substituted with one or more, preferably            1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from            the group consisting of —R^(y), fluoro, —OH, —NH₂, lower            alkoxy, fluoro substituted lower alkoxy, lower alkylthio,            fluoro substituted lower alkylthio, mono-alkyl amino,            di-alkyl amino, and cycloalkylamino, and wherein lower            alkenyl or lower alkynyl are optionally substituted with one            or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3            substituents selected from the group consisting of —R^(y),            fluoro, —OH, —NH₂, lower alkyl, fluoro substituted lower            alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower            alkylthio, fluoro substituted lower alkylthio, mono-alkyl            amino, di-alkyl amino, and cycloalkylamino;        -   wherein each —R^(y) is selected from the group consisting of            cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein            cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are            optionally substituted with one or more, preferably 1, 2, 3,            4 or 5, also 1, 2, or 3 substituents selected from the group            consisting of halogen, —OH, —NH₂, —NO₂, —CN, lower alkyl,            fluoro substituted lower alkyl, lower alkoxy, fluoro            substituted lower alkoxy, lower alkylthio, fluoro            substituted lower alkylthio, mono-alkyl amino, di-alkyl            amino, and cycloalkylamino.

“Lower alkoxy” denotes the group —OR^(z), where R^(z) is lower alkyl.“Substituted lower alkoxy” denotes lower alkoxy in which R^(z) is loweralkyl substituted with one or more substituents as indicated herein, forexample, in the description of compounds of Formula I (includingFormulae Ia, Ib, Ig and all sub-embodiments thereof), includingdescriptions of substituted cycloalkyl, cycloheteroalkyl, aryl andheteroaryl, attached at any available atom to produce a stable compound.Preferably, substitution of lower alkoxy is with 1, 2, 3, 4, or 5substituents, also 1, 2, or 3 substituents. For example “fluorosubstituted lower alkoxy” denotes lower alkoxy in which the lower alkylis substituted with one or more fluoro atoms, where preferably the loweralkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3fluoro atoms. While it is understood that substitutions on alkoxy areattached at any available atom to produce a stable compound,substitution of alkoxy is such that —O—, —S—, or —N-(except where N is aheteroaryl ring atom), are not bound to the alkyl carbon bound to thealkoxy —O—. Further, where alkoxy is described as a substituent ofanother moiety, the alkoxy oxygen is not bound to a carbon atom that isbound to an —O—, —S—, or —N— of the other moiety (except where N is aheteroaryl ring atom), or to an alkene or alkyne carbon of the othermoiety.

“Lower alkylthio” denotes the group —SR^(aa), where R^(aa) is loweralkyl. “Substituted lower alkylthio” denotes lower alkylthio in whichR^(aa) is lower alkyl substituted with one or more substituents asindicated herein, for example, in the description of compounds ofFormula I (including Formulae Ia, Ib, Ig and all sub-embodimentsthereof), including descriptions of substituted cycloalkyl,cycloheteroalkyl, aryl and heteroaryl, attached at any available atom toproduce a stable compound. Preferably, substitution of lower alkylthiois with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents. Forexample “fluoro substituted lower alkylthio” denotes lower alkylthio inwhich the lower alkyl is substituted with one or more fluoro atoms,where preferably the lower alkylthio is substituted with 1, 2, 3, 4 or 5fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood thatsubstitutions on alkylthio are attached at any available atom to producea stable compound, substitution of alkylthio is such that —O—, —S—, or—N-(except where N is a heteroaryl ring atom), are not bound to thealkyl carbon bound to the alkylthio —S—. Further, where alkylthio isdescribed as a substituent of another moiety, the alkylthio sulfur isnot bound to a carbon atom that is bound to an —O—, —S—, or —N— of theother moiety (except where N is a heteroaryl ring atom), or to an alkeneor alkyne carbon of the other moiety.

“Amino” or “amine” denotes the group —NH₂. “Mono-alkylamino” denotes thegroup —NHR^(bb) where R^(bb) is lower alkyl. “Di-alkylamino” denotes thegroup —NR^(bb)R^(cc), where R^(bb) and R^(cc) are independently loweralkyl. “Cycloalkylamino” denotes the group —NR^(dd)R^(ee), where R^(dd)and R^(ee) combine with the nitrogen to form a 5-7 memberedheterocycloalkyl, where the heterocycloalkyl may contain an additionalheteroatom within the ring, such as —O—, —N—, or —S—, and may also befurther substituted with lower alkyl. Examples of 5-7 memberedheterocycloalkyl include, but are not limited to, piperidine,piperazine, 4-methylpiperazine, morpholine, and thiomorpholine. While itis understood that when mono-alkylamino, di-alkylamino, orcycloalkylamino are substituents on other moieties that are attached atany available atom to produce a stable compound, the nitrogen ofmono-alkylamino, di-alkylamino, or cycloalkylamino as substituents isnot bound to a carbon atom that is bound to an —O—, —S—, or —N— of theother moiety.

As used herein, the term c-kit-mediated disease or condition refers to adisease or condition in which the biological function of c-kit affectsthe development and/or course of the disease or condition, and/or inwhich modulation of c-kit alters the development, course, and/orsymptoms. For example, mutations in the c-kit gene such as the W42, Wv,and W41 mutations reported by Herbst et al al (J. Biol. Chem., 1992,267: 13210-13216) confer severe, intermediate, and mild phenotypiccharacteristics, respectively. These mutations attenuate the intrinsictyrosine kinase activity of the receptor to different degrees and aremodels for the effect of modulation of c-kit activity. A c-kit mediateddisease or condition includes a disease or condition for which c-kitinhibition provides a therapeutic benefit, e.g. wherein treatment withc-kit inhibitors, including compounds described herein, provides atherapeutic benefit to the subject suffering from or at risk of thedisease or condition.

As used herein, the term c-fins-mediated disease or condition refers toa disease or condition in which the biological function of c-fms affectsthe development and/or course of the disease or condition, and/or inwhich modulation of c-fms alters the development, course, and/orsymptoms. For example, the Csflr⁻/Csflr⁻ mutant mouse of Dai et al(Blood, 2002, 99: 111-120) which lacks c-fms is an animal model fordiseases or conditions wherein c-fms activity has been abolished. Ac-fms mediated disease or condition includes a disease or condition forwhich c-fms inhibition provides a therapeutic benefit, e.g. whereintreatment with c-fms inhibitors, including compounds described herein,provides a therapeutic benefit to the subject suffering from or at riskof the disease or condition.

As used herein, the term “composition” refers to a formulation suitablefor administration to an intended animal subject for therapeuticpurposes that contains at least one pharmaceutically active compound andat least one pharmaceutically acceptable carrier or excipient.

The term “pharmaceutically acceptable” indicates that the indicatedmaterial does not have properties that would cause a reasonably prudentmedical practitioner to avoid administration of the material to apatient, taking into consideration the disease or conditions to betreated and the respective route of administration. For example, it iscommonly required that such a material be essentially sterile, e.g., forinjectibles.

In the present context, the terms “therapeutically effective” and“effective amount” indicate that the materials or amount of material iseffective to prevent, alleviate, or ameliorate one or more symptoms of adisease or medical condition, and/or to prolong the survival of thesubject being treated.

Reference to particular amino acid residues in human c-kit polypeptideis defined by the numbering corresponding to the Kit sequence in GenBankNP_(—)000213 (SEQ ID NO:1). Reference to particular nucleotide positionsin a nucleotide sequence encoding all or a portion of c-kit is definedby the numbering corresponding to the sequence provided in GenBankNM_(—)000222 (SEQ ID NO:2). Reference to particular amino acid residuesin human c-fms polypeptide is defined by the numbering corresponding tothe FMS precursor sequence in GenBank NP 005202 (SEQ ID NO:3). Referenceto particular nucleotide positions in a nucleotide sequence encoding allor a portion of c-fms is defined by the numbering corresponding to thesequence provided in GenBank NM 005211 (SEQ ID NO:4).

The terms “kit”, “c-kit”, and “c-Kit” mean an enzymatically activekinase that contains a portion with greater than 90% amino acid sequenceidentity to amino acid residues including the ATP binding site offull-length c-kit (e.g., human c-kit, e.g., the sequence NP_(—)000213,SEQ ID NO:1), for a maximal alignment over an equal length segment; orthat contains a portion with greater than 90% amino acid sequenceidentity to at least 200 contiguous amino acids of native c-kit andretains kinase activity. Preferably the sequence identity is at least95, 97, 98, 99, or even 100%. Preferably the specified level of sequenceidentity is over a sequence at least 100-500, at least 200-400, or atleast 300 contiguous amino acid residues in length. Unless indicated tothe contrary, the term includes reference to wild-type c-kit, allelicvariants, and mutated forms (e.g., having activating mutations).

The terms “fins”, “c-fins”, “FMS”, and “c-Fms” mean an enzymaticallyactive kinase that contains a portion with greater than 90% amino acidsequence identity to amino acid residues including the ATP binding siteof full-length c-fms (e.g. human c-fins, e.g. residues 20-972 of GenBanksequence NP 005202, SEQ ID NO:3), for a maximal alignment over an equallength segment; or that contains a portion with greater than 90% aminoacid sequence identity to at least 200 contiguous amino acids of nativec-fms and retains kinase activity. Preferably the sequence identity isat least 95, 97, 98, 99, or 100%. Preferably the specified level ofsequence identity is over a sequence at least 100-150, at least 200-400,or at least 300 contiguous amino acid residues in length. Unlessindicated to the contrary, the term includes wild-type c-fms, allelicvariants, and mutated forms (e.g. having activating mutations). The term“pFMS” refers to phosphorylated c-fms. The term “c-fins activity” refersto a biological activity of c-fms, particularly including kinaseactivity. The abbreviation “M-CSF” refers to the ligand for the c-fmsRPTK, and the abbreviation “SCF” refers to the ligand for the c-KitRPTK.

The term “c-kit kinase domain” refers to a reduced length c-kit (i.e.,shorter than a full-length c-kit by at least 100 amino acids) thatincludes the kinase catalytic region in c-kit. The term “c-fms kinasedomain” refers to a c-fms of reduced length (i.e., shorter than afull-length c-fms by at least 100 amino acids) that includes the kinasecatalytic region of c-fms. Highly preferably for use in this invention,the kinase domain retains kinase activity, preferably at least 60, 70,80, 90, or 100% of the native c-fms kinase activity. The term “thekinase” or terms of similar import relate to either c-kit or c-fins.

As used herein, the terms “ligand” and “modulator” are used equivalentlyto refer to a compound that changes (i.e., increases or decreases) theactivity of a target biomolecule, e.g., an enzyme such as a kinase orkinase. Generally a ligand or modulator will be a small molecule, where“small molecule” refers to a compound with a molecular weight of 1500daltons or less, or preferably 1000 daltons or less, 800 daltons orless, or 600 daltons or less.

In the context of compounds binding to a target, the term “greateraffinity” indicates that the compound binds more tightly than areference compound, or than the same compound in a reference condition,i.e., with a lower dissociation constant. In particular embodiments, thegreater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500,1000, or 10.000-fold greater affinity.

Also in the context of compounds binding to a biomolecular target, theterm “greater specificity” indicates that a compound binds to aspecified target to a greater extent than to another biomolecule orbiomolecules that may be present under relevant binding conditions,where binding to such other biomolecules produces a different biologicalactivity than binding to the specified target. Typically, thespecificity is with reference to a limited set of other biomolecules,e.g., in the case of c-kit or c-fins, other tyrosine kinases or evenother type of enzymes. In particular embodiments, the greaterspecificity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, or1000-fold greater specificity.

As used herein in connection with binding compounds or ligands, the term“specific for c-kit kinase”, “specific for c-kit”, and terms of likeimport mean that a particular compound binds to c-kit to a statisticallygreater extent than to other kinases that may be present in a particularsample. Also, where biological activity other than binding is indicated,the term “specific for c-kit” indicates that a particular compound hasgreater biological effect associated with binding c-kit than to othertyrosine kinases, e.g., kinase activity inhibition. Preferably, thespecificity is also with respect to other biomolecules (not limited totyrosine kinases) that may be present in a particular sample. The term“specific for c-fms kinase”, “specific for c-fms”, and terms of likeimport mean that a particular compound binds to c-fms to a statisticallygreater extent than to other kinases that may be present in a particularsample. Also, where biological activity other than binding is indicated,the term “specific for c-fins” indicates that a particular compound hasgreater biological effect associated with binding c-fms than to othertyrosine kinases, e.g., kinase activity inhibition. Preferably, thespecificity is also with respect to other biomolecules (not limited totyrosine kinases) that may be present in a particular sample.

As used herein in connection with test compounds, binding compounds, andmodulators (ligands), the term “synthesizing” and like terms meanschemical synthesis from one or more precursor materials.

By “assaying” is meant the creation of experimental conditions and thegathering of data regarding a particular result of the experimentalconditions. For example, enzymes can be assayed based on their abilityto act upon a detectable substrate. A compound or ligand can be assayedbased on its ability to bind to a particular target molecule ormolecules.

As used herein, the term “modulating” or “modulate” refers to an effectof altering a biological activity, especially a biological activityassociated with a particular biomolecule such as c-kit or c-fms. Forexample, an agonist or antagonist of a particular biomolecule modulatesthe activity of that biomolecule, e.g., an enzyme.

The term “c-kit activity” refers to a biological activity of c-kit,particularly including kinase activity. The term “c-fins activity”refers to a biological activity of c-fms, particularly including kinaseactivity.

In the context of the use, testing, or screening of compounds that areor may be modulators, the term “contacting” means that the compound(s)are caused to be in sufficient proximity to a particular molecule,complex, cell, tissue, organism, or other specified material thatpotential binding interactions and/or chemical reaction between thecompound and other specified material can occur.

As used herein in connection with amino acid or nucleic acid sequence,the term “isolate” indicates that the sequence is separated from atleast a portion of the amino acid and/or nucleic acid sequences withwhich it would normally be associated.

In connection with amino acid or nucleic sequences, the term “purified”indicates that the particular molecule constitutes a significantlygreater proportion of the biomolecules in a composition than in a priorcomposition, e.g., in a cell culture. The greater proportion can be2-fold, 5-fold, 10-fold or more greater.

I. General

In one aspect, the present invention concerns compounds of Formula I,Formula Ia, Formula Ib, Formula Ig, Formula II, Formula IIa, FormulaIIb, Formula IIc, Formula IId, Formula IIe, Formula IIf, Formula IIg,Formula IIh, Formula III, Formula IIj, Formula IIk, Formula IIm, FormulaIIn, Formula IIo, Formula IIp, or Formula III, and all sub-embodimentsthereof, that are inhibitors of c-kit, c-fins, or both c-kit and c-fms,and the use of the compounds in treating diseases that are mediated byc-kit, c-fins, or both c-kit and c-fms.

Exemplary Diseases Associated with c-Kit.

The compounds described herein are useful for treating disorders relatedto c-kit e.g., diseases related to unregulated kinase signaltransduction, including cell proliferative disorders, fibrotic disordersand metabolic disorders, among others. As described in more detail belowand in Lipson et al., U.S. 20040002534 (U.S. application Ser. No.10/600, 868, filed Jun. 23, 2003) which is incorporated herein byreference in its entirety, cell proliferative disorders which can betreated by the present invention include cancers, and mast cellproliferative disorders.

The presence of c-kit has also been associated with a number ofdifferent types of cancers, as described below. In addition, theassociation between abnormalities in c-kit and disease are notrestricted to cancer. As such, c-kit has been associated withmalignancies, including mast cell tumors, small cell lung cancer,testicular cancer, gastrointestinal stromal tumors (GISTs),glioblastoma, astrocytoma, neuroblastoma, carcinomas of the femalegenital tract, sarcomas of neuroectodermal origin, colorectal carcinoma,carcinoma in situ, Schwann cell neoplasia associated withneurofibromatosis, acute myelocytic leukemia, acute lymphocyticleukemia, chronic myelogenous leukemia, mastocytosis, melanoma, andcanine mast cell tumors, and inflammatory diseases, including asthma,rheumatoid arthritis, allergic rhinitis, multiple sclerosis,inflammatory bowel syndrome, transplant rejection, andhypereosinophilia.

Exemplary Malignant Diseases Associated with c-Kit

Aberrant expression and/or activation of c-kit has been implicated in avariety of cancers. Evidence for a contribution of c-kit to neoplasticpathology includes its association with leukemias and mast cell tumors,small cell lung cancer, testicular cancer, and some cancers of thegastrointestinal tract and central nervous system. In addition, c-kithas been implicated in playing a role in carcinogenesis of the femalegenital tract (Inoue, et al., 1994, Cancer Res. 54(11):3049-3053),sarcomas of neuroectodermal origin (Ricotti, et al., 1998, Blood91:2397-2405), and Schwann cell neoplasia associated withneurofibromatosis (Ryan, et al., 1994, J. Neuro. Res. 37:415-432). Itwas found that mast cells are involved in modifying the tumormicroenvironment and enhancing tumor growth (Yang et al., 2003, J ClinInvest. 112:1851-1861; Viskochil, 2003, J Clin Invest. 112:1791-1793).Thus, c-kit is a useful target in treating neurofibromatosis as well asmalignant tumors.

Small cell lung carcinoma: c-kit kinase receptor has been found to beaberrantly expressed in many cases of small cell lung carcinoma (SCLC)cells (Hibi, et al., 1991, Oncogene 6:2291-2296). Thus, as an example,inhibition of c-kit kinase can be beneficial in treatment of SCLC, e.g.,to improve the long term survival of patients with SCLC.

Leukemias: SCF binding to the c-kit protects hematopoietic stem andprogenitor cells from apoptosis (Lee, et al., 1997, J. Immunol.159:3211-3219), thereby contributing to colony formation andhematopoiesis. Expression of c-kit is frequently observed in acutemyelocytic leukemia (AML), and in some cases of acute lymphocyticleukemia (ALL) (for reviews, see Sperling, et al., 1997, Haemat82:617-621; Escribano, et al., 1998, Leuk. Lymph. 30:459-466). Althoughc-kit is expressed in the majority of AML cells, its expression does notappear to be prognostic of disease progression (Sperling, et al, 1997,Haemat 82:617-621). However, SCF protected AML cells from apoptosisinduced by chemotherapeutic agents (Hassan, et al., 1996, Acta. Hem.95:257-262). Inhibition of c-kit by the present invention will enhancethe efficacy of these agents and can induce apoptosis of AML cells.

The clonal growth of cells from patients with myelodysplastic syndrome(Sawada, et al., 1996, Blood 88:319-327) or chronic myelogenous leukemia(CML) (Sawai, et al., 1996, Exp. Hem. 2:116-122) was found to besignificantly enhanced by SCF in combination with other cytokines. CMLis characterized by expansion of Philadelphia chromosome positive cellsof the marrow (Verfaillie, et al., Leuk. 1998, 12:136-138), whichappears to primarily result from inhibition of apoptotic death (Jones,Curr. Opin. One. 1997, 9:3-7). The product of the Philadelphiachromosome, p210^(BCR-ABL), has been reported to mediate inhibition ofapoptosis (Bedi, et al., Blood 1995, 86:1148-1158). Since p210^(BCR-ABL)and c-kit both inhibit apoptosis and p62^(dok) has been suggested as asubstrate (Carpino, et al., Cell 1997, 88:197-204), clonal expansionmediated by these kinases may occur through a common signaling pathway.However, c-kit has also been reported to interact directly withp210^(BCR-ABL) (Hallek, et al., Brit. J Haem. 1996, 94:5-16), whichsuggests that c-kit has a more causative role in CML pathology.Therefore, inhibition of c-kit will be useful in the treatment of theabove disorders.

Gastrointestinal cancers: Normal colorectal mucosa does not expressc-kit (Bellone, et al., 1997, J. Cell Physiol. 172:1-11). However, c-kitis frequently expressed in colorectal carcinoma (Bellone, et al., 1997,J. Cell Physiol. 172: 1-11), and autocrine loops of SCF and c-kit havebeen observed in several colon carcinoma cell lines (Toyota, et al.,1993, Turn Biol 14:295-302; Lahm, et al., 1995, Cell Growth &Differ6:1111-1118; Bellone, et al., 1997, J. Cell Physiol. 172:1-11).Furthermore, disruption of the autocrine loop by the use of neutralizingantibodies (Lahm, et al., 1995, Cell Growth & Differ. 6:1111-1118) anddownregulation of c-kit and/or SCF significantly inhibits cellproliferation (Lahm, et al., 1995, Cell Growth & Differ 6:1111-1118;Bellone, et al., 1997, J. Cell Physiol. 172:1-11).

SCF/c-kit autocrine loops have been observed in gastric carcinoma celllines (Turner, et al., 1992, Blood 80:374-381; Hassan, et al., 1998,Digest. Dis. Science 43:8-14), and constitutive c-kit activation alsoappears to be important for gastrointestinal stromal tumors (GISTs).GISTs are the most common mesenchymal tumor of the digestive system.More than 90% of GISTs express c-kit, which is consistent with theputative origin of these tumor cells from interstitial cells of Cajal(ICCs) (Hirota, et al., 1998, Science 279:577-580). ICCs are thought toregulate contraction of the gastrointestinal tract, and patients lackingc-kit in their ICCs exhibited a myopathic form of chronic idiopathicintestinal pseudo-obstruction (Isozaki, et al., 1997, Amer. J. of Gast.9 332-334). The c-kit expressed in GISTs from several different patientswas observed to have mutations in the intracellular juxtamembrane domainleading to constitutive activation of c-kit (Hirota, et al., 1998,Science 279:577-580). Hence, inhibition of c-kit kinase will be anefficacious means for the treatment of these cancers.

Testicular cancers: Male germ cell tumors have been histologicallycategorized into seminomas, which retain germ cell characteristics, andnonseminomas which can display characteristics of embryonaldifferentiation. Both seminomas and nonseminomas are thought to initiatefrom a preinvasive stage designated carcinoma in situ (CIS) (Murty, etal., 1998, Sem. Oncol. 25:133-144). Both c-kit and SCF have beenreported to be essential for normal gonadal development duringembryogenesis (Loveland, et al., 1997, J. Endocrinol 153:337-344). Lossof either the receptor or the ligand resulted in animals devoid of germcells. In postnatal testes, c-kit has been found to be expressed inLeydig cells and spermatogonia, while SCF was expressed in Sertoli cells(Loveland, et al., 1997, J. Endocrinol 153:337-344). Testicular tumorsdevelop from Leydig cells with high frequency in transgenic miceexpressing human papilloma virus 16 (HPV16) E6 and E7 oncogenes (Kondoh,et al., 1991, J. Virol. 65:3335-3339; Kondoh, et al., 1994, J. Urol.152:2151-2154). These tumors express both c-kit and SCF, and anautocrine loop may contribute to the tumorigenesis (Kondoh, et al.,1995, Oncogene 10:341-347) associated with cellular loss of functionalp53 and the retinoblastoma gene product by association with E6 and E7(Dyson, et al., 1989, Science 243:934-937; Werness, et al., 1990,Science 248:76-79; Scheffner, et al., 1990, Cell 63:1129-1136).Defective signaling mutants of SCF (Kondoh, et al., 1995, Oncogene10:341-347) or c-kit (Li, et al., 1996, Canc. Res. 56:4343-4346)inhibited formation of testicular tumors in mice expressing HPV16 E6 andE7. The c-kit kinase activation is pivotal to tumorigenesis in theseanimals and thus modulation of the c-kit kinase pathway by the presentinvention will prevent or treat such disorders.

Expression of c-kit in germ cell tumors shows that the receptor isexpressed by the majority of carcinomas in situ and seminomas, but c-kitis expressed in only a minority of nonseminomas (Strohmeyer, et al.,1991, Canc. Res. 51:1811-1816; Rajpert-de Meyts, et al., 1994, Int. J.Androl. 17:85-92; Izquierdo, et al., 1995, J. Pathol. 177:253-258;Strohmeyer, et al., 1995, J. Urol. 153:511-515; Bokenmeyer, et al.,1996, J. Cancer Res. Clin. Oncol. 122:301-306; Sandlow, et al., 1996, J.Androl. 17:403-408). Therefore, inhibition of c-kit kinase provides ameans for treating these disorders.

CNS cancers: SCF and c-kit are expressed throughout the CNS ofdeveloping rodents, and the pattern of expression indicates a role ingrowth, migration and differentiation of neuroectodermal cells.Expression of both receptor and ligand have also been reported in theadult brain (Hamel, et al., 1997, J. Neuro-One. 35:327-333). Expressionof c-kit has also been observed in normal human brain tissue (Tada, etal. 1994, J. Neuro 80:1063-1073). Glioblastoma and astrocytoma, whichdefine the majority of intracranial tumors, arise from neoplastictransformation of astrocytes (Levin, et al., 1997, Principles & Practiceof Oncology:2022-2082). Expression of c-kit has been observed inglioblastoma cell lines and tissues (Berdel, et al., 1992, Canc. Res.52:3498-3502; Tada, et al. 1994, J. Neuro 80:1063-1073; Stanulla, etal., 1995, Act Neuropath 89:158-165).

Cohen, et al., 1994, Blood 84:3465-3472 reported that all 14neuroblastoma cell lines examined contained c-kit/SCF autocrine loops,and expression of both the receptor and ligand were observed in 45% oftumor samples examined. In two cell lines, anti-c-kit antibodiesinhibited cell proliferation, suggesting that the SCF/c-kit autocrineloop contributed to growth (will Cohen, et al., 1994, Blood84:3465-3472). Hence, c-kit kinase inhibitors can be used to treat thesecancers.

Exemplary Mast Cell Diseases Involving c-kit

Excessive activation of c-kit is also associated with diseases resultingfrom an over-abundance of mast cells. Mastocytosis is the term used todescribe a heterogeneous group of disorders characterized by excessivemast cell proliferation (Metcalfe, 1991, J. Invest. Derm 93:2 S-4S;Golkar, et al., 1997, Lancet 349:1379-1385). Elevated c-kit expressionwas reported on mast cells from patients with aggressive mastocytosis(Nagata, et al., 1998, Leukemia 12:175-181).

Additionally, mast cells and eosinophils represent key cells involved inallergy, inflammation and asthma (Thomas, et al., 1996, Gen. Pharmacol27:593-597; Metcalfe, et al., 1997, Physiol Rev 77:1033-1079; Naclerio,et al., 1997, JAMA 278:1842-1848; Costa, et al., 1997, JAMA278:1815-1822). SCF, and hence c-kit, directly and indirectly regulatesactivation of both mast cells and eosinophils, thereby influencing theprimary cells involved in allergy and asthma through multiplemechanisms. Because of this mutual regulation of mast cell andeosinophil function, and the role that SCF can play in this regulation,inhibition of c-kit can be used to treat allergy-associated chronicrhinitis, inflammation and asthma.

Mastocytosis: SCF (also known as mast cell growth factor) stimulation ofc-kit has been reported to be essential for the growth and developmentof mast cells (Hamel, et al., 1997, J. Neuro-One. 35:327-333; Kitamura,et al., 1995, Int. Arch. Aller. Immunol. 107:54-56). Mice with mutationsof c-kit that attenuate its signaling activity have exhibitedsignificantly fewer mast cells in their skin (Tsujimura, 1996, PatholInt 46:933-938). Excessive activation of c-kit can be associated withdiseases resulting from an over abundance of mast cells.

Mastocytosis is limited to the skin in the majority of patients, but caninvolve other organs in 15-20% of patients (Valent, 1996, Wein/KlinWochenschr 108:385-397; Golkar, et al., 1997, Lancet 349:1379-1385).Even among patients with systemic mastocytosis, the disease can rangefrom having a relatively benign prognosis to aggressive mastocytosis andmast cell leukemia. (Valent, 1996, Wein/Klin Wochenschr 108:385-397;Golkar, et al., 1997, Lancet 349:1379-1385). c-kit has been observed onmalignant mast cells from canine mast cell tumors (London, et al., 1996,J. Compar. Pathol. 115:399-414), as well as on mast cells from patientswith aggressive systemic mastocytosis (Baghestanian, et al., 1996,Leuk.:116-122; Castells, et al., 1996, J. Aller. Clin. Immunol.98:831-840).

SCF has been shown to be expressed on stromal cells as a membrane-boundprotein, and its expression can be induced by fibrogenic growth factorssuch as PDGF. It has also been shown to be expressed on keratinocytes asa membrane-bound protein in normal skin. However, in the skin ofpatients with mastocytosis, an increased amount of soluble SCF has beenobserved (Longley, et al., 1993, New Engl. J. Med. 328:1302-1307).

Mast cell chymase has been reported to cleave membrane-associated SCF toa soluble and biologically active form. This mast cell-mediated processcan generate a feedback loop to enhance mast cell proliferation andfunction (Longley, et al., 1997, Proc. Natl. Acad. Sci. 94:9017-9021),and may be important for the etiology of mastocytosis. Transgenic miceoverexpressing a form of SCF that could not be proteolytically releasedfrom keratinocytes did not develop mastocytosis, while similar animalsexpressing normal SCF in keratinocytes exhibited a phenotype resemblinghuman cutaneous mastocytosis (Kunisada, et al., 1998, J. Exp. Med.187:1565-1573). Formation of large amounts of soluble SCF can contributeto the pathology associated with mastocytosis in some patients and thepresent invention can treat or prevent such disorders by modulating theinteraction between SCF and c-kit kinase. Several different mutations ofc-kit that resulted in constitutive kinase activity have been found inhuman and rodent mast cell tumor cell lines (Furitsu, et al., 1993, J.Clin. Invest. 92:1736-1744; Tsujimura, et al., 1994, Blood 9:2619-2626;Tsujimura, et al., 1995, Int. Arch. Aller. Immunol 106:377-385;Tsujimura, 1996, Pathol Int 46:933-938). In addition, activatingmutations of the c-kit gene have been observed in peripheral mononuclearcells isolated from patients with mastocytosis and associatedhematologic disorders (Nagata, et al., 1998, Mastocytosis Leuk12:175-181), and in mast cells from a patient with urticaria pigmentosaand aggressive mastocytosis (Longley, et al., 1996, Nat. Gen.12:312-314). Inhibition of c-kit kinase will therefore prove to have anexcellent therapeutic role in the treatment of these disorders.

In some patients, activating mutations of c-kit may be responsible forthe pathogenesis of the disease and these patients can be treated, ortheir diseases prevented, by modulation of the SCF interaction withc-kit kinase. SCF activation of c-kit as been shown to prevent mast cellapoptosis which may be critical for maintaining cutaneous mast cellhomeostasis (Iemura, et al., 1994, Amer. J. Pathol 144:321-328; Yee, etal., 1994, J. Exp. Med. 179:1777-1787; Mekori, et al., 1994, J. Immunol.153:2194-2203; Mekori, et al., 1995, Int. Arch. Allergy Immunol.107:137-138). Inhibition of mast cell apoptosis can lead to the mastcell accumulation associated with mastocytosis. Thus, observation ofc-kit activation resulting from overexpression of the receptor,excessive formation of soluble SCF, or mutations of the c-kit gene thatconstitutively activate its kinase, provides a rationale that inhibitionof the kinase activity of c-kit will decrease the number of mast cellsand provide benefit for patients with mastocytosis.

For cells with activating c-kit mutations, it was found that inhibitorsof c-kit inhibit or even kill the cells (Ma et al., 2000, J InvestDermatol. 114:392-394), particularly for mutations in the regulatoryregion (Ma et al., 2002, Blood 99:1741-1744). Ma et al., 2002, alsoshowed that for mutations in the catalytic region, inhibitors STI571(Gleevec) and SU9529 did not inhibit the cells, such that additionaltypes of c-kit inhibitors are useful. Thus, c-kit inhibitors can be usedagainst both wild-type c-kit as well as c-kit having mutations, e.g.,activating mutations in the regulatory region and/or catalytic region.

Asthma & Allergy: Mast cells and eosinophils represent key cells inparasitic infection, allergy, inflammation, and asthma (Thomas, et al.,1996, Gen. Pharmacol 27:593-597; Metcalfe, et al., 1997, Physiol Rev77:1033-1079; Holgate, 1997, CIBA Found. Symp.; Naclerio, et al, 1997,JAMA 278:1842-1848; Costa, et al., 1997, JAMA 778:1815-1822). SCF hasbeen shown to be essential for mast cell development, survival andgrowth (Kitamura, et al., 1995, Int. Arch. Aller. Immunol. 107:54-56;Metcalfe, et al., 1997, Physiol Rev 77:1033-1079). In addition, SCFcooperates with the eosinophil-specific regulator, IL-5, to increase thedevelopment of eosinophil progenitors (Metcalf, et al., 1998, Proc.Natl. Acad. Sci., USA 95:6408-6412). SCF has also been reported toinduce mast cells to secrete factors (Okayama, et al., 1997, Int. Arch.Aller. Immunol. 114:75-77; Okayama, et al., 1998, Eur. J. Immunol.28:708-715) that promote the survival of eosinophils (Kay, et al., 1997,Int. Arch. Aller. Immunol. 113:196-199), which may contribute tochronic, eosinophil-mediated inflammation (Okayama, et al., 1997, Int.Arch. Aller. Immunol. 114:75-77; Okayama, et al., 1998, Eur. J. Immunol.28:708-715). In this regard, SCF directly and indirectly regulatesactivation of both mast cells and eosinophils.

SCF induces mediator release from mast cells, as well as priming thesecells for IgE-induced degranulation (Columbo, et al., 1992, J. Immunol.149:599-602) and sensitizing their responsiveness to eosinophil-derivedgranule major basic protein (Furuta, et al., 1998, Blood 92:1055-1061).Among the factors released by activated mast cells are IL-5, GM-CSF andTNF-α, which influence eosinophil protein secretion (Okayama, et al.,1997, Int. Arch. Aller. Immunol. 114:75-77; Okayama, et al., 1998, Eur.J. Immunol. 28:708-715). In addition to inducing histamine release frommast cells (Luckacs, et al., 1996, J. Immunol. 156:3945-3951; Hogaboam,et al., 1998, J. Immunol. 160:6166-6171), SCF promotes the mast cellproduction of the eosinophil chemotactic factor, eotaxin (Hogaboam, etal., 1998, J. Immunol. 160:6166-6171), and eosinophil infiltration(Luckacs, et al., 1996, J. Immunol. 156:3945-3951).

SCF also directly influences the adhesion of both mast cells (Dastych,et al., 1994, J. Immunol. 152:213-219; Kinashi, et al., 1994, Blood83:1033-1038) and eosinophils (Yuan, et al., 1997, J. Exp. Med.186:313-323), which in turn, regulates tissue infiltration. Thus, SCFcan influence the primary cells involved in allergy and asthma throughmultiple mechanisms. Currently, corticosteroids are the most effectivetreatment for chronic rhinitis and inflammation associated with allergy(Naclerio, et al., 1997, JAMA 278:1842-1848; Meltzer, 1997, Aller.52:33-40). These agents work through multiple mechanisms includingreduction of circulating and infiltrating mast cells and eosinophils,and diminished survival of eosinophils associated with inhibition ofcytokine production (Meltzer, 1997, Aller. 52:33-40). Steroids have alsobeen reported to inhibit the expression of SCF by fibroblasts andresident connective tissue cells, which leads to diminished mast cellsurvival (Finotto, et al., 1997, J. Clin. Invest. 99 1721-1728). Becauseof the mutual regulation of mast cell and eosinophil function, and therole that SCF can play in this regulation, inhibition of c-kit kinasewill provide a means to treat allergy-associated chronic rhinitis,inflammation and asthma.

Inflammatory arthritis (e.g. rheumatoid arthritis): Due to theassociation of mast cells with the arthritic process (Lee et al., 2002,Science 297:1689-1692), c-kit provides a useful target for prevention,delay, and/or treatment of inflammatory arthritis, such as rheumatoidarthritis.

Multiple sclerosis: Mast cells have been shown to play an extensive rolein autoimmune diseases, as demonstrated in the mouse model of multiplesclerosis (MS), experimental allergic encephalomyelitis (EAE). Mastcells were indicated to be required for full manifestation of thedisease. Secor et al., 2000, J Exp Med 191:813-821. Thus, c-kit alsoprovides a useful target for the prevention, delay, and/or treatment ofmultiple sclerosis.

Exemplary Diseases Associated with c-Fms

The presence of c-fms has been associated with a number of differenttypes of diseases. As such, c-fms has been associated with immunedisorders, including rheumatoid arthritis, systemic lupus erythematosis(SLE), and transplant rejection; inflammatory diseases including, butnot limited to, osteoarthritis, inflammatory bowel syndrome, ulcerativecolitis, Crohn's disease, chronic obstructive pulmonary disease (COPD),emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophageactivation syndrome), multicentric reticulohistiocytosis, andatherosclerosis; metabolic disorders, including, but not limited to,Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia,obesity, and lipolysis; disorders of bone structure, mineralization andbone formation and resorption, including, but not limited to,osteoporosis, increased risk of fracture, Paget's disease,hypercalcemia, infection-mediated osteolysis (e.g., osteomyelitis),peri-prosthetic or wear-debris-mediated osteolysis, and metastasis ofcancer to bone; kidney and genitourinary diseases, including, but notlimited to, endometriosis, nephritis (e.g. glomerulonephritis,interstitial nephritis, Lupus nephritis), tubular necrosis,diabetes-associated renal complications (e.g. diabetic nephropathy), andrenal hypertrophy; disorders of the central nervous system, including,but not limited to, multiple sclerosis, stroke, Alzheimer's disease andParkinson's disease; inflammatory and chronic pain, including, but notlimited to bone pain; and cancers, including, but not limited to,multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia(CML), prostate cancer, breast cancer, ovarian cancer, melanoma,glioblastoma multiforme, metastasis of tumors to other tissues, andother chronic myeloproliferative diseases such as myelofibrosis.

Aberrant expression and/or activation of c-fms has been implicated inacute myeloid leukemia, AML (Ridge et al, Proc. Nat. Acad. Sci., 1990,87:1377-1380). Mutations at codon 301 are believed to lead to neoplastictransformation by ligand independence and constitutive tyrosine kinaseactivity of the receptor. The tyrosine residue at codon 969 has beenshown to be involved in a negative regulatory activity, which isdisrupted by amino acid substitutions. Accordingly, c-fms mutations aremost prevalent (20%) in chronic myelomonocytic leukemia and AML type M4(23%), both of which are characterized by monocytic differentiation.

A condition related to AML is chronic myeloid leukemia (CML). During themyeloid blast crisis (BC) of CML, non-random additional chromosomeabnormalities occur in over 80% of patients. However, these cytogeneticchanges have been reported to precede the clinical signs of CML-BC byseveral months to years suggesting that other biological events mayparticipate in the multistep process of acute transformation of CML. Theautocrine production of growth factors has been shown to occur inseveral hematological malignancies and particularly in AML. Specchia etal [Br J Haematol. 1992 March; 80(3):310-6] have demonstrated that IL-1beta gene is expressed in almost all cases of CML in myeloid blastcrisis, and that a high proportion of cases showed constitutiveexpression of the M-CSF gene. Many of the same patients in the Specchiaet al study demonstrated simultaneous co-expression of c-fms. Afterexposure of leukemic cells to phorbol myristate acetate (PMA), releaseof M-CSF protein was documented in three of five patients studied;however, no significant interleukin-3 (IL-3), granulocyte-macrophagecolony-stimulating factor (GM-CSF) or granulocyte colony-stimulatingfactor (G-CSF), was detected in these patients. This demonstrates thatdifferent patterns of growth factors secretion exist in AML and CML, andthat distinct molecular events are likely involved in the control ofleukemic proliferation.

The observation that production of M-CSF, the major macrophage growthfactor, is increased in tissues during inflammation (Le Meur et al, J.Leukocyte Biology. 2002; 72:530-537) provides a role for c-fms incertain diseases. For example, COPD is characterized by airflowlimitation that is not fully reversible. The airflow limitation isusually progressive and associated with an abnormal inflammatoryresponse of the lungs to noxious particles or gases. The chronicinflammation of COPD is observed through the airways, parenchyma, andpulmonary vasculature. The inflammatory cell population consists ofneutrophils, macrophages, and T lymphocytes, along with eosinophils insome patients. Macrophages are postulated to play an orchestrating rolein COPD inflammation by releasing mediators such as TNF-α, IL-8 andLTB4, which are capable of damaging lung structures and/or sustainingneutrophilic inflammation.

Further, M-CSF/Fms signaling is critical to osteoclast formation andsurvival of osteoclast precursors. For example, estrogen loss inmenopause results in increased M-CSF and thus increased osteoclastnumber and bone resorption which leads to increased risk of fracture andosteoporosis. Accordingly, blockage of this signal is a target for theinhibition of bone resorption (Teitelbaum, Science. 2000; 289:1504;Rohan, Science. 2000; 289:1508.)

Atherosclerosis, an inflammatory disease of the vessel walls, isassociated with significant morbidity and mortality. A effect for c-fmsinhibition in the treatment and prevention of atherosclerosis depends onseveral observations (Libby, Nature. 2002; 420:868-874.) First,monocytes resident in the arterial intima increase expression ofscavenger receptors and internalize modified lipoproteins. The resultinglipid-laden macrophages develop into foam cells characteristic of theatherosclerotic lesion. Macrophages in atheroma secrete cytokines andgrowth factors involved in lesion progression. Additionally, macrophagesreplicate within the intima. Through c-fins, M-CSF activates thetransition from monocyte to lipid-laden macrophage and augmentsexpression of scavenger receptor A. Indeed, atherosclerotic plaquesover-express M-CSF which is critical for atherosclerotic progression.Mice deficient in M-CSF have been found to experience less severeatherosclerosis than mice with normal M-CSF (Rajavashisth, et. al., J.Clin. Invest. 1998; 101:2702-2710; Qiao, et. al., Am. J. Path. 1997;150:1687-1699). Accordingly, inhibitors of c-fms disrupt M-CSFsignaling, compromising monocyte to macrophage foam cell progression,macrophage survival and replication, and cytokine signaling thatparticipates in lesion progression.

The role of M-CSF and c-fms in emphysema appears to involve theregulation of elastin metabolism through control of matrixmetalloproteins. M-CSF has a role in the modulation of the accumulationand function of alveolar macrophages (AMs) in vivo (Shibata et al, Blood2001, 98: pp. 2845-2852). Osteopetrotic (Op/Op) mice have no detectableM-CSF and show variable tissue-specific reductions in macrophagenumbers. Accordingly, it was hypothesized that AMs would be decreased innumber and have altered function in Op/Op mice because of the absence ofM-CSF. Shibata et al found that lung macrophages identified in lungsections were decreased in number in 20-day-old Op/Op mice but not Op/Opmice older than 4 months compared with findings in age-matchedlittermate controls. The numbers of AMs recovered by bronchoalveolarlavage (BAL) were also reduced in young but not adult Op/Op micecompared with controls. Importantly, AMs of Op/Op mice spontaneouslyrelease higher levels of matrix metalloproteinases (MMPs) than AMs ofcontrols. Consistent with an increased release of MMP, Op/Op mice haveabnormal elastin deposition and spontaneously develop emphysema in theabsence of molecular or cellular evidence of lung inflammation.Accordingly, the modulation of metalloelastase activity in macrophagesby M-CSF may control the degradation of elastin fibers in lungs or bloodvessels.

Metastatic cancer cells cause bone destruction, with associatedfracture, pain, deformation, and hypercalcaemia, due to production ofosteoclasticogenic factors including M-CSF by tumor cells (Clohisy etal, Clin. Orthop. 2000, 373: 104-14). Binding of M-CSF to the c-fmsproduct stimulates formation of osteoclasts and osteolytic activity(Kodama et al, J. Exp., Med. 1991, 173: 269-72; Feng et al,Endocrinology 2002, 143: 4868-74). Accordingly, inhibition of osteoclastactivity at the level of c-fms offers a compelling target foramelioration of bone metastasis.

Macrophage accumulation is a prominent feature in many forms ofglomerulonephritis. Local proliferation of macrophages within the kidneyhas been described in human and experimental glomerulonephritis and mayhave an important role in augmenting the inflammatory response. Isbel etal (Nephrol Dial Transplant 2001, 16: 1638-1647) examined therelationship between local macrophage proliferation and renal expressionof M-CSF. Glomerular and tubulointerstitial M-CSF expression was foundto be up-regulated in human glomerulonephritis, being most prominent inproliferative forms of disease. Because this correlates with localmacrophage proliferation, it suggests that increased renal M-CSFproduction plays an important role in regulating local macrophageproliferation in human glomerulonephritis. In a model of renalinflammation (UUO—unilateral ureteric obstruction) anti-c-fms antibodytreatment reduced macrophage accumulation (Le Meur et.al., J LeukocyteBiology, 2002, 72: 530-537). Accordingly, inhibition of c-fms offers atarget for therapeutic intervention in glomerulonephritis.

Insulin resistance and obesity are hallmark of type II diabetes andthere is a strong correlation between insulin resistance and abdominalvisceral fat accumulation (Bjomtrop, Diabetes Metab. Res. Rev., 1999,15: 427-441). Current evidence indicates that macrophages accumulatingin adipose tissue release TNF-a and other factors that cause adipocytechanges (hypertrophy, lipolysis, reduced insulin sensitivity) and alsopromote insulin resistance in surrounding tissues. Therefore, macrophageaccumulation in type 2 diabetes is important for disease progression.Accordingly, inhibition of c-fms has potential in preventing thedevelopment of insulin resistance and hyperglycemia.

Dewar et al. have recently demonstrated that the kinase inhibitorimatinib also specifically targets the macrophage colony stimulatingfactor receptor, c-fms, at therapeutic concentrations. Although thisfinding has important implications with regard to potential side effectsin patients currently receiving imatinib therapy, these results suggestthat imatinib may also be useful in the treatment of diseases wherec-fins is implicated. This includes breast and ovarian cancer andinflammatory conditions such as rheumatoid arthritis. Dewar et al. alsospeculate that imatinib may be used in diseases where bone destructionoccurs due to excessive osteoclast activity, such as in the haematologicmalignancy, multiple myeloma (Dewar et al., Cell Cycle 2005,4(7):851-3).

To determine the importance of M-CSF in driving macrophage proliferationduring acute rejection, Jose et al. blocked the M-CSF receptor, c-fms,in a mouse model of acute renal allograft rejection. They observed thatthe severity of tubulointerstitial rejection was reduced in thetreatment group as shown by decreased tubulitis and tubular cellproliferation. Macrophage proliferation during acute allograft rejectionis dependent on the interaction of M-CSF with its receptor c-fms. Theyindicate that this pathway plays a significant and specific role in theaccumulation of macrophages within a rejecting renal allograft (Jose etal., Am J Transplant 2003, 3(3):294-300).

Further, modulators of both c-fms and c-kit function can be used againstdiseases such as those indicated above, where in some instances, thedual activity of the modulator for both c-fms and c-kit providesdistinct advantages in treating such diseases. The complementaryactivities provided by a single compound would provide added benefitsover compounds targeting one or the other activity, or separatecompounds targeting these activities. For example, by attenuatingrelease of macrophage chemo-attractants by mast cells or mast cellchemoattractants by macrophages, these anti-inflammatory effects wouldsynergize with the concomitant inhibition of intrinsic cellularfunction. Limitations in co-administration are absent in a dualinhibitor. Further, the dual activity may result in much lower effectivedoses for treatment.

Exemplary Diseases Associated with TrkA and TrkB

TrkA:

Target kinase TrkA (i.e., neurotrophic tyrosine kinase, receptor,type 1) is a 140 kDa tyrosine kinase encoded by chromosome 1q21-q22(symbol: NTRK1). TrkA inhibitors may be useful in treating pain (e.g.chronic pain, neuropathic pain), cancer (e.g. prostate cancer, lungcancer, myeloid leukemia, pancreatic cancer), allergic disorders (e.g.asthma), arthritis, diabetic retinopathy, macular degeneration andpsoriasis.

TrkA is a plasma member receptor composed of an extracellular domain(responsible for high affinity binding to nerve growth factor, NGF), atransmembrane segment and an intracellular protein tyrosine kinasedomain (responsible to transmit the NGF signal to initiate andcoordinate neuronal responses). NGF binding induces TrkA clustering onthe membrane and activates the kinase. The kinase initiates a cascade ofprotein phosphorylation events through multiple pathways includingSHC/Ras/MAPK, PI3K and PLCg1. A TrkA kinase inhibitor would not preventNGF/TrkA binding, but could prevent down-stream signal transduction.

Nerve Growth Factor (NGF) is produced by a number of tissues andinflammatory cells during tissue injury and host immune response. Itinitiates and maintains hypersensitivity to incoming stimulus(hyperalgesia) and the perception of non-noxious stimuli (allodynia).Through its high-affinity receptor TrkA, NGF increases the excitationstate of sensory neurons leading to the central nervous system(peripheral sensitization), and increases transmitter release from thedorsal spinal cord (central sensitization). In clinical trials, a singleNGF subcutaneous injection generated local hyperalgesia persisting up to7 weeks. At doses above 0.1 microgram/kg, NGF caused muscle pain thatvaried from mild to moderate, primarily in the bulbar and truncalmusculature. Intravenous NGF produced earlier and more pronouncedsystemic effects (Petty et al, 1994, Ann Neurol. 36: 244-6). Conversely,TrkA kinase inhibitors could be used to treat diseases of enhancedstates of nociception.

In Complete Freund's Adjuvant (CFA)-induced hind-paw inflammation,spinal nerve ligation and streptozoticin-induced neuropathic painmodels, a single intraperitoneal injection of anti-NGF reversedestablished tactile allodynia from day 3 to day 7 following treatment.In the mouse CCI model, anti-NGF reversed tactile allodynia whenadministered 2 weeks after surgery. Repeated administration of thisantibody to CCI mice for 3 weeks produced a sustained reversal oftactile allodynia (Wild et al, 2007, J. Pharmacol. Exp. Ther.322:282-287).

Prostate tumors that have metastasized to bone frequently induce bonepain which can be difficult to fully control as it seems to be drivensimultaneously by inflammatory, neuropathic, and tumorigenic mechanisms.Anti-NGF produced a significant reduction in both early and late stagebone cancer pain-related behaviors. This therapy did not influencetumor-induced bone remodeling, osteoblast proliferation,osteoclastogenesis, tumor growth, or markers of sensory or sympatheticinnervation in the skin or bone. All nerve fibers that innervate thebone express TrkA and p75, and these are the receptors through which NGFsensitizes and/or activates nociceptors (Halvorson et al, 2005, CancerRes. 65:9426-35).

In patients with mild asthma due to exposure to cat allergen, NGFexpression was strongly induced in epithelial cells, fibroblasts, bloodvessels, and a few infiltrating cells. TrkA mRNA and protein levels inbronchial biopsies were increased significantly after allergen exposurein infiltrating mast cells before the onset of symptoms (Kassel et al,2001, Clin Exp Allergy 31:1432-40).

The late phase reaction in asthma following allergen provocation isdominated by an influx of activated eosinophils into the bronchiallumen, which correlates with the release of eosinophilic products intothe airways to increase disease severity. The viability and activationof eosinophils from patients with mild asthma were significantlyenhanced after NGF stimulation. Addition of neutralizing anti-NGFantibodies ex vivo abrogated the effects (Nassentein et al, 2003, J ExpMed 198:455-467). TrkA kinase inhibitors could decrease this paracrineloop between the respiratory tract and infiltrating mast cells as wellas endobronchial eosinophils, and thus be useful for the treatment ofasthma and other allergic disorders.

TrkB:

Target kinase TrkB (i.e., neurotrophic tyrosine kinase, receptor, type2) is a 145 kDa tyrosine kinase encoded by chromosome 9q22.1 (symbol:NTRK2). TrkB inhibitors may be useful in treating various cancers andtheir metastases (e.g. prostate cancer, lung cancer, Wilms tumors,neuroblastoma, and pancreatic cancer), and various neuropathies (e.g.stroke, multiple sclerosis, transverse myelitis, and encephalitis).

In clinical trials with recombinant BDNF, paresthesia was developed atthe site of subcutaneous injection (Coulie et al, 2000, Gastroenterology119:41-50). Intrathecal infusion of BDNF in humans also inducedparesthesia and warmth as side effects (Ochs et al, 2000, AmyotrophLateral Scler Other Motor Neuron Disord. 1:201-6). Chronic paresthesiais often a symptom of an underlying neurological disease or traumaticnerve damage. Paresthesia can be caused by disorders affecting thecentral nervous system, such as stroke and transient ischemic attacks(mini-strokes), multiple sclerosis, transverse myelitis, andencephalitis. Since BDNF binds to TrkB specifically with high affinitythese neuropath effects are mediated through TrkB signaling. Thus Trkbkinase inhibitors could be used to treat certain patients withneuropathy.

BDNF is known to act at the synapses between primary sensory and spinaldorsal horn neurons to affect pain transmission during inflammation. Theprimary afferent is the only source of BDNF in the spinal cord, and itis up-regulated in the dorsal root ganglion (DRG) by peripheral NGF afew days after inflammation, and is transported and released into thesuperficial dorsal horn in an activity-dependent manner. TrkB expressionin the dorsal horn also increases for a few days after inflammation.These findings suggest that BDNF may act during the restricted period inthe early phase of inflammation. Through TrkB, BDNF activates twodistinct channels: (1) transient receptor potential canonicals (TRPC3),which produces a slow response by opening of a non-selective cationchannel; and (2) Na+ channel, which mediates a rapid depolarization inthe hippocampus. These channels have been strongly associated withinflammatory pain. Anti-BDNF significantly increased the withdrawalthreshold in CFA-treated rats, a model of inflammatory pain. Since theswelling at the site of CFA injection was not affected by antiserum, theresidual component might be due to peripheral sensitization (Matayoshiet al, 2005, J. Physiol. 569:685-95).

In patients with neuroblastomas, co-expression of TrkB and BDNF,co-expression of TrkB with N-Myc amplification, and expression oftruncated TrkB are found to be associated with poorer clinical outcome(Nakagawara et al, 1994, Mol Cell Biol. 14:759-767). Co-expression ofTrkB with its ligand BDNF could generate a positive feedback loopthrough autocrine and paracrine loops. Also TrkB truncations found inthese tumors generate activated forms of the intracellular proteintyrosine kinase. The constitutively active TrkB signals through multiplepathways to promote cancer initiation, progression and metastasis. Thesetruncated TrkB kinases were also found in hepatocellular carcinoma (Yanget al, 2005, Cancer. Res 65:219-225). Thus TrkB inhibitors could be usedto treat a sub-population of cancer patients with an activated TrkBpathway.

In patients with pancreatic cancer, TrkB expression is correlated withperineural invasion, positive retroperitoneal margin, and shorterlatency to development of liver metastasis (Sclabas et al, 2005, Clin.Cancer. Res V11:440-449). Mechanistically, TrkB activates the PI3Kpathway to suppress anoikis (apoptosis resulting from loss ofcell-matrix interactions) which is one of the physiological barriers tometastasis. TrkB kinase inhibition could break down resistance toanoikis of metastasizing tumors (Douma et al, 2004, Nature 430:1034-9).Therefore, TrkB inhibitors could have utility in a broad range of tumortypes.

Exemplary Diseases Associated with HGK

HGK:

Target kinase HGK (i.e., Hematopoietic progenitor kinase/Germinal centerkinase-like Kinase, aka mitogen-activated protein kinase kinase kinasekinase 4) is a 130 kDa serine/threonine kinase encoded by chromosome2q111.2-q12 (symbol: MAP4K4). It is a member of the humanSTE20/mitogen-activated protein kinase kinase kinase kinase (MAP4K)family of serine/threonine kinases and is the human ortholog of mouseNIK (Nck-interacting kinase). The N-terminus of the mature HGK proteinhas a catalytic kinase domain that shares 47% and 48% amino acidsequence identity to the catalytic domain of Hematopoietic progenitorkinase 1 (HPK1) and Germinal center kinase (GCK), respectively. Yao etal. (J. Biol. Chem. 274: 2118-2125, 1999) identified 2 HGK isoforms, oneof which has no proline-rich domains, and another, longer variant thatcontains such domains and appears to be expressed in brain only.Northern blot analysis revealed expression of 3 HGK transcripts ofapproximately 4.6, 6.5, and 8.5 kb in heart, brain, skeletal muscle,pancreas, placenta, liver, lung, and kidney. By Western blot analysiswith a polyclonal antibody, Yao et al. (J. Biol. Chem. 274: 2118-2125,1999) found that the 130-kD protein is expressed in multiple cell lines.

Expression of HGK in transfected cell lines resulted in strong JNKactivation and, in turn, c-jun transcriptional activity (Yao et al. J.Biol. Chem. 274: 2118-2125, 1999). HGK-induced JNK activation wasinhibited by dominant-negative MAP2K4, MAP2K7, and TAK1 mutants.TNF-alpha also stimulated HGK kinase activity. HGK was identified as aputative effect of Rap2 to activate JNK (Machida et al. J. Biol. Chem.279: 15711-15714, 2004). This link establishes HGK as a potential targetfor a range of metabolic indications, since the JNK pathway clearlyantagonizes insulin signaling. An HGK inhibitor could re-sensitize fatand muscle cells to insulin.

HGK is found to be broadly expressed in human tumor cells and canmodulate cellular transformation, invasion, and adhesion (Wright et al.Mol. Cell. Biol. 23: 2068-2082, 2003). Wright et al showed HGK to behighly expressed in most tumor cell lines relative to normal tissue. Anactive role for this kinase in transformation was suggested by aninhibition of H-Ras(V 12)-induced focus formation by expression ofinactive, dominant-negative mutants of HGK in both fibroblast andepithelial cell lines. Expression of an inactive mutant of HGK alsoinhibited the anchorage-independent growth of cells yet had no effect onproliferation in monolayer culture. Expression of HGK mutants modulatedintegrin receptor expression and had a striking effect on hepatocytegrowth factor-stimulated epithelial cell invasion. Together, theseresults suggest an important role for HGK in cell transformation andinvasiveness. More recently, a small interfering RNA screen formodulators of tumor cell motility identifies MAP4K4 as a promigratorykinase (Collins et al. Proc. Natl. Acad. Sci. USA, 103: 3775-3780,2006). Collins et al. showed that the knockdown of the HGK transcriptinhibited the migration of multiple carcinoma cell lines, indicating abroad role in cell motility, and potently suppressed the invasion ofSKOV-3 cells in vitro. The effect of HGK on cellular migration was foundto be mediated through JNK kinase, independent of API activation anddownstream transcription. Accordingly, small molecule inhibition ofc-Jun N-terminal kinase suppressed SKOV-3 cell migration, underscoringthe potential therapeutic utility of mitogen-activated protein kinasepathway inhibition in cancer progression (Collins et al. Proc. Natl.Acad. Sci. USA, 103: 3775-3780, 2006). These studies strongly supportHGK as a target in a broad range of oncology indications. In particular,an HGK inhibitor could have utility in blocking the migration, invasionand metastasis in many different tumor types.

Activation of T-cells by antigens initiates a complex series ofsignal-transduction events that are critical for immune responses. Macket al. (Immunol. Lett. 96, 129-145, 2005) developed a genetic screen tosurvey the functional roles of kinases in antigen mediated T-cellactivation and identified 19 protein kinases that were previouslyimplicated in T-cell signaling processes and 12 kinases that were notpreviously linked to T-cell activation, including HGK. siRNA studiesshowed a role for HGK in antigen mediated T-cell responses in Jurkat andprimary T-cells. In addition, by analyzing multiple promoter elementsusing reporter assays, Mack et al. have shown that MAP4K4 is implicatedin the activation of the TNF-alpha promoter. Therefore, inhibition ofHGK could have broad therapeutic utility for T-cell-mediated autoimmunediseases.

Insulin-regulated glucose transporter GLUT4 is a key modulator of wholebody glucose homeostasis, and its selective loss in adipose tissue orskeletal muscle causes insulin resistance and diabetes. Using an RNAinterference-based screen, Tang et al. (Proc Natl Acad Sci USA.103:2087-2092, 2006) found 4 negative regulators of insulin-responsiveglucose transport in mouse adipocytes: Pctk1, Pftk1, Ikbka (CHUK), andHGK. HGK suppressed expression of adipogenic transcription factors,C/EBPA, C/EBPB, and PPARG, and it suppressed surface expression of GLUT4(SLC2A4), resulting in attenuated membrane hexose transport activity.RNA interference-mediated depletion of HGK early in differentiationenhanced adipogenesis and triglyceride deposition; in fullydifferentiated adipocytes, loss of HGK upregulated GLUT4 expression.Conversely, conditions that inhibited adipogenesis, such as TNF-alphatreatment or PPARG depletion, markedly upregulated HGK. Tang et al.(Proc Natl Acad Sci USA. 103:2087-2092, 2006) concluded thatMAP4K4-dependent signaling inhibited PPARG-responsive gene expression,adipogenesis, and insulin-stimulated glucose transport. Furthermore,TNF-alpha signaling to down-regulate GLUT4 is impaired in the absence ofHGK, indicating that HGK expression is required for optimal TNF-alphaaction. This study further supports HGK as a target in metabolicdisease, and suggests a role for HGK inhibition in ameliorating thepathology in adipocytes.

In a separate study (Bouzakri and Zierath J. Biol. Chem. 282:7783-7789,2007), using small interfering RNA (siRNA) to suppress the expression ofHGK protein 85% in primary human skeletal muscle cells,TNF-alpha-induced insulin resistance on glucose uptake was completelyprevented. HGK silencing inhibited TNF-alpha-induced negative signalinginputs by preventing excessive JNK and ERK-1/2 phosphorylation, as wellas IRS-1 serine phosphorylation. These results highlight theHGK/JNK/ERK/IRS module in the negative regulation of insulin signalingto glucose transport in response to TNF-alpha. Depletion of HGK alsoprevented TNF-alpha-induced insulin resistance on AKT and the AKTsubstrate 160 (AS160), providing evidence that appropriate insulinsignaling inputs for glucose metabolism were rescued. The authorssuggested that strategies to inhibit HGK may be efficacious in theprevention of TNF-alpha-induced inhibitory signals that cause skeletalmuscle insulin resistance on glucose metabolism in humans. Moreover, inmyotubes from insulin-resistant type II diabetic patients, siRNA againstHGK restored insulin action on glucose uptake to levels observed inhealthy subjects. This study further supports HGK as a target inmetabolic diseases such as type II diabetes, and suggests a role for HGKinhibition in ameliorating the pathology in muscle cells.

HGK inhibitors may be useful in treating metabolic indications,including re-sensitizing fat and muscle cells to insulin, amelioratingthe pathology in adipocytes, ameliorating the pathology in muscle cells,and type II diabetes; a broad range of oncology indications, includingblocking the migration, invasion and metastasis in many different tumortypes; and T-cell mediated autoimmune diseases.

II. Production of c-kit and c-fms Related Polypeptides

The native and mutated kinase polypeptides described herein may bechemically synthesized in whole or part using techniques that arewell-known in the art (see, e.g., Creighton (1983) Biopolymers22(1):49-58).

Alternatively, methods which are well known to those skilled in the artcan be used to construct expression vectors containing the native ormutated kinase polypeptide coding sequence and appropriatetranscriptional/translational control signals. These methods include invitro recombinant DNA techniques, synthetic techniques and in vivorecombination/genetic recombination. See, for example, the techniquesdescribed in Maniatis, T (1989). Molecular cloning: A laboratory Manual.Cold Spring Harbor Laboratory, New York. Cold Spring Harbor LaboratoryPress; and Ausubel, F. M. et al. (1994) Current Protocols in MolecularBiology. John Wiley & Sons, Secaucus, N.J.

A variety of host-expression vector systems may be utilized to expressthe kinase coding sequence. These include but are not limited tomicroorganisms such as bacteria transformed with recombinantbacteriophage DNA, plasmid DNA or cosmid DNA expression vectorscontaining the kinase domain coding sequence; yeast transformed withrecombinant yeast expression vectors containing the kinase domain codingsequence; insect cell systems infected with recombinant virus expressionvectors (e.g. baculovirus) containing the kinase domain coding sequence;plant cell systems infected with recombinant virus expression vectors(e.g. cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) ortransformed with recombinant plasmid expression vectors (e.g. Tiplasmid) containing the kinase domain coding sequence; or animal cellsystems. The expression elements of these systems vary in their strengthand specificities.

Depending on the host/vector system utilized, any of a number ofsuitable transcription and translation elements, including constitutiveand inducible promoters, may be used in the expression vector. Forexample, when cloning in bacterial systems, inducible promoters such aspL of bacteriophage λ, plac, ptrp, ptac (ptrp-lac hybrid promoter) andthe like may be used; when cloning in insect cell systems, promoterssuch as the baculovirus polyhedrin promoter may be used; when cloning inplant cell systems, promoters derived from the genome of plant cells(e.g. heat shock promoters; the promoter for the small subunit ofRUBISCO; the promoter for the chlorophyll a/b binding protein) or fromplant viruses (e.g. the 35S RNA promoter of CaMV; the coat proteinpromoter of TMV) may be used; when cloning in mammalian cell systems,promoters derived from the genome of mammalian cells (e.g.metallothionein promoter) or from mammalian viruses (e.g. the adenoviruslate promoter; the vaccinia virus 7.5K promoter) may be used; whengenerating cell lines that contain multiple copies of the kinase domainDNA, SV4O-, BPV- and EBV-based vectors may be used with an appropriateselectable marker.

Exemplary methods describing methods of DNA manipulation, vectors,various types of cells used, methods of incorporating the vectors intothe cells, expression techniques, protein purification and isolationmethods, and protein concentration methods are disclosed in detail inPCT publication WO 96/18738. This publication is incorporated herein byreference in its entirety, including any drawings. Those skilled in theart will appreciate that such descriptions are applicable to the presentinvention and can be easily adapted to it.

III. Binding Assays

The methods of the present invention can involve assays that are able todetect the binding of compounds to a target molecule. Such binding is ata statistically significant level, preferably with a confidence level ofat least 90%, more preferably at least 95, 97, 98, 99% or greaterconfidence level that the assay signal represents binding to the targetmolecule, i.e., is distinguished from background. Preferably controlsare used to distinguish target binding from non-specific binding. Alarge variety of assays indicative of binding are known for differenttarget types and can be used for this invention.

Binding compounds can be characterized by their effect on the activityof the target molecule. Thus, a “low activity” compound has aninhibitory concentration (IC₅₀) or effective concentration (EC₅₀) ofgreater than 1 μM under standard conditions. By “very low activity” ismeant an IC₅₀ or EC₅₀ of above 100 μM under standard conditions. By“extremely low activity” is meant an IC₅₀ or EC₅₀ of above 1 mM understandard conditions. By “moderate activity” is meant an IC₅₀ or EC₅₀ of200 nM to 1 μM under standard conditions. By “moderately high activity”is meant an IC₅₀ or EC₅₀ of 1 nM to 200 nM. By “high activity” is meantan IC₅₀ or EC₅₀ of below 1 nM under standard conditions. The IC₅₀ orEC₅₀ is defined as the concentration of compound at which 50% of theactivity of the target molecule (e.g. enzyme or other protein) activitybeing measured is lost or gained relative to the range of activityobserved when no compound is present. Activity can be measured usingmethods known to those of ordinary skill in the art, e.g., by measuringany detectable product or signal produced by occurrence of an enzymaticreaction, or other activity by a protein being measured.

By “background signal” in reference to a binding assay is meant thesignal that is recorded under standard conditions for the particularassay in the absence of a test compound, molecular scaffold, or ligandthat binds to the target molecule. Persons of ordinary skill in the artwill realize that accepted methods exist and are widely available fordetermining background signal.

By “standard deviation” is meant the square root of the variance. Thevariance is a measure of how spread out a distribution is. It iscomputed as the average squared deviation of each number from its mean.For example, for the numbers 1, 2, and 3, the mean is 2 and the varianceis:

$\sigma^{2} = {\frac{\left( {1 - 2} \right)^{2} + \left( {2 - 2} \right)^{2} + \left( {3 - 2} \right)^{2}}{3} = {0.667.}}$

Surface Plasmon Resonance

Binding parameters can be measured using surface plasmon resonance, forexample, with a BIAcore® chip (Biacore, Japan) coated with immobilizedbinding components. Surface plasmon resonance is used to characterizethe microscopic association and dissociation constants of reactionbetween an sFv or other ligand directed against target molecules. Suchmethods are generally described in the following references which areincorporated herein by reference. Vely F. et al., (2000) BIAcore®analysis to test phosphopeptide-SH2 domain interactions, Methods inMolecular Biology. 121:313-21; Liparoto et al., (1999) Biosensoranalysis of the interleukin-2 receptor complex, Journal of MolecularRecognition. 12:316-21; Lipschultz et al., (2000) Experimental designfor analysis of complex kinetics using surface plasmon resonance,Methods. 20(3):310-8; Malmqvist., (1999) BIACORE: an affinity biosensorsystem for characterization of biomolecular interactions, BiochemicalSociety Transactions 27:335-40; Alfthan, (1998) Surface plasmonresonance biosensors as a tool in antibody engineering, Biosensors &Bioelectronics. 13:653-63; Fivash et al., (1998) BIAcore formacromolecular interaction, Current Opinion in Biotechnology. 9:97-101;Price et al.; (1998) Summary report on the ISOBM TD-4 Workshop: analysisof 56 monoclonal antibodies against the MUC1 mucin. Tumour Biology 19Suppl 1:1-20; Malmqvist et al, (1997) Biomolecular interaction analysis:affinity biosensor technologies for functional analysis of proteins,Current Opinion in Chemical Biology. 1:378-83; O'Shannessy et al.,(1996) Interpretation of deviations from pseudo-first-order kineticbehavior in the characterization of ligand binding by biosensortechnology, Analytical Biochemistry. 236:275-83; Malmborg et al., (1995)BIAcore as a tool in antibody engineering, Journal of ImmunologicalMethods. 183:7-13; Van Regenmortel, (1994) Use of biosensors tocharacterize recombinant proteins, Developments in BiologicalStandardization. 83:143-51; and O'Shannessy, (1994) Determination ofkinetic rate and equilibrium binding constants for macromolecularinteractions: a critique of the surface plasmon resonance literature,Current Opinions in Biotechnology. 5:65-71.

BIAcore® uses the optical properties of surface plasmon resonance (SPR)to detect alterations in protein concentration bound to a dextran matrixlying on the surface of a gold/glass sensor chip interface, a dextranbiosensor matrix. In brief, proteins are covalently bound to the dextranmatrix at a known concentration and a ligand for the protein is injectedthrough the dextran matrix. Near infrared light, directed onto theopposite side of the sensor chip surface is reflected and also inducesan evanescent wave in the gold film, which in turn, causes an intensitydip in the reflected light at a particular angle known as the resonanceangle. If the refractive index of the sensor chip surface is altered(e.g. by ligand binding to the bound protein) a shift occurs in theresonance angle. This angle shift can be measured and is expressed asresonance units (RUs) such that 1000 RUs is equivalent to a change insurface protein concentration of 1 ng/mm². These changes are displayedwith respect to time along the y-axis of a sensorgram, which depicts theassociation and dissociation of any biological reaction.

High Throughput Screening (HTS) Assays

HTS typically uses automated assays to search through large numbers ofcompounds for a desired activity. Typically HTS assays are used to findnew drugs by screening for chemicals that act on a particular enzyme ormolecule. For example, if a chemical inactivates an enzyme it mightprove to be effective in preventing a process in a cell which causes adisease. High throughput methods enable researchers to assay thousandsof different chemicals against each target molecule very quickly usingrobotic handling systems and automated analysis of results.

As used herein, “high throughput screening” or “HTS” refers to the rapidin vitro screening of large numbers of compounds (libraries); generallytens to hundreds of thousands of compounds, using robotic screeningassays. Ultra high-throughput Screening (uHTS) generally refers to thehigh-throughput screening accelerated to greater than 100,000 tests perday.

To achieve high-throughput screening, it is advantageous to housesamples on a multicontainer carrier or platform. A multicontainercarrier facilitates measuring reactions of a plurality of candidatecompounds simultaneously. Multi-well microplates may be used as thecarrier. Such multi-well microplates, and methods for their use innumerous assays, are both known in the art and commercially available.

Screening assays may include controls for purposes of calibration andconfirmation of proper manipulation of the components of the assay.Blank wells that contain all of the reactants but no member of thechemical library are usually included. As another example, a knowninhibitor (or activator) of an enzyme for which modulators are sought,can be incubated with one sample of the assay, and the resultingdecrease (or increase) in the enzyme activity used as a comparator orcontrol. It will be appreciated that modulators can also be combinedwith the enzyme activators or inhibitors to find modulators whichinhibit the enzyme activation or repression that is otherwise caused bythe presence of the known the enzyme modulator.

Measuring Enzymatic and Binding Reactions During Screening Assays

Techniques for measuring the progression of enzymatic and bindingreactions, e.g., in multicontainer carriers, are known in the art andinclude, but are not limited to, the following.

Spectrophotometric and spectrofluorometric assays are well known in theart. Examples of such assays include the use of colorimetric assays forthe detection of peroxides, as described in Gordon, A. J. and Ford, R.A., (1972) The Chemist's Companion: A Handbook Of Practical Data,Techniques, And References, John Wiley and Sons, N.Y., Page 437.

Fluorescence spectrometry may be used to monitor the generation ofreaction products. Fluorescence methodology is generally more sensitivethan the absorption methodology. The use of fluorescent probes is wellknown to those skilled in the art. For reviews, see Bashford et al.,(1987)Spectrophotometry and Spectrofluorometry: A Practical Approach,pp. 91-114, IRL Press Ltd.; and Bell, (1981) Spectroscopy InBiochemistry, Vol. I, pp. 155-194, CRC Press.

In spectrofluorometric methods, enzymes are exposed to substrates thatchange their intrinsic fluorescence when processed by the target enzyme.Typically, the substrate is nonfluorescent and is converted to afluorophore through one or more reactions. As a non-limiting example,SMase activity can be detected using the Amplex® Red reagent (MolecularProbes, Eugene, Oreg.). In order to measure sphingomyelinase activityusing Amplex® Red, the following reactions occur. First, SMasehydrolyzes sphingomyelin to yield ceramide and phosphorylcholine.Second, alkaline phosphatase hydrolyzes phosphorylcholine to yieldcholine. Third, choline is oxidized by choline oxidase to betaine.Finally, H₂O₂, in the presence of horseradish peroxidase, reacts withAmplex® Red to produce the fluorescent product, Resorufin, and thesignal therefrom is detected using spectrofluorometry.

Fluorescence polarization (FP) is based on a decrease in the speed ofmolecular rotation of a fluorophore that occurs upon binding to a largermolecule, such as a receptor protein, allowing for polarized fluorescentemission by the bound ligand. FP is empirically determined by measuringthe vertical and horizontal components of fluorophore emission followingexcitation with plane polarized light. Polarized emission is increasedwhen the molecular rotation of a fluorophore is reduced. A fluorophoreproduces a larger polarized signal when it is bound to a larger molecule(i.e. a receptor), slowing molecular rotation of the fluorophore. Themagnitude of the polarized signal relates quantitatively to the extentof fluorescent ligand binding. Accordingly, polarization of the “bound”signal depends on maintenance of high affinity binding.

FP is a homogeneous technology and reactions are very rapid, takingseconds to minutes to reach equilibrium. The reagents are stable, andlarge batches may be prepared, resulting in high reproducibility.Because of these properties, FP has proven to be highly automatable,often performed with a single incubation with a single, premixed,tracer-receptor reagent. For a review, see Owicki et al., (1997),Application of Fluorescence Polarization Assays in High-ThroughputScreening, Genetic Engineering News, 17:27.

FP is particularly desirable since its readout is independent of theemission intensity (Checovich, W. J., et al., (1995) Nature 375:254-256;Dandliker, W. B., et al., (1981) Methods in Enzymology 74:3-28) and isthus insensitive to the presence of colored compounds that quenchfluorescence emission. FP and FRET (see below) are well-suited foridentifying compounds that block interactions between sphingolipidreceptors and their ligands. See, for example, Parker et al., (2000)Development of high throughput screening assays using fluorescencepolarization: nuclear receptor-ligand-binding and kinase/phosphataseassays, J Biomol Screen 5:77-88.

Fluorophores derived from sphingolipids that may be used in FP assaysare commercially available. For example, Molecular Probes (Eugene,Oreg.) currently sells sphingomyelin and one ceramide fluorophores.These are, respectively,N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosylphosphocholine (BODIPY® FL C5-sphingomyelin);N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoyl)sphingosylphosphocholine (BODIPY® FL C12-sphingomyelin); andN-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosine(BODIPY® FL C5-ceramide). U.S. Pat. No. 4,150,949, (Immunoassay forgentamicin), discloses fluorescein-labelled gentamicins, includingfluoresceinthiocarbanyl gentamicin. Additional fluorophores may beprepared using methods well known to the skilled artisan.

Exemplary normal-and-polarized fluorescence readers include thePOLARION® fluorescence polarization system (Tecan A G, Hombrechtikon,Switzerland). General multiwell plate readers for other assays areavailable, such as the VERSAMAX® reader and the SPECTRAMAX® multiwellplate spectrophotometer (both from Molecular Devices).

Fluorescence resonance energy transfer (FRET) is another useful assayfor detecting interaction and has been described. See, e.g., Heim etal., (1996) Curr. Biol. 6:178-182; Mitra et al., (1996) Gene 173:13-17;and Selvin et al., (1995) Meth. Enzymol. 246:300-345. FRET detects thetransfer of energy between two fluorescent substances in closeproximity, having known excitation and emission wavelengths. As anexample, a protein can be expressed as a fusion protein with greenfluorescent protein (GFP). When two fluorescent proteins are inproximity, such as when a protein specifically interacts with a targetmolecule, the resonance energy can be transferred from one excitedmolecule to the other. As a result, the emission spectrum of the sampleshifts, which can be measured by a fluorometer, such as a fMAX multiwellfluorometer (Molecular Devices, Sunnyvale Calif.).

Scintillation proximity assay (SPA) is a particularly useful assay fordetecting an interaction with the target molecule. SPA is widely used inthe pharmaceutical industry and has been described (Hanselman et al.,(1997) J. Lipid Res. 38:2365-2373; Kahl et al., (1996) Anal. Biochem.243:282-283; Undenfriend et al., (1987) Anal. Biochem. 161:494-500). Seealso U.S. Pat. Nos. 4,626,513 and 4,568,649, and European Patent No.0,154,734. One commercially available system uses FLASHPLATE®scintillant-coated plates (NEN Life Science Products, Boston, Mass.).

The target molecule can be bound to the scintillator plates by a varietyof well known means. Scintillant plates are available that arederivatized to bind to fusion proteins such as GST, His6 or Flag fusionproteins. Where the target molecule is a protein complex or a multimer,one protein or subunit can be attached to the plate first, then theother components of the complex added later under binding conditions,resulting in a bound complex.

In a typical SPA assay, the gene products in the expression pool willhave been radiolabeled and added to the wells, and allowed to interactwith the solid phase, which is the immobilized target molecule andscintillant coating in the wells. The assay can be measured immediatelyor allowed to reach equilibrium. Either way, when a radiolabel becomessufficiently close to the scintillant coating, it produces a signaldetectable by a device such as a TOPCOUNT NXT®microplate scintillationcounter (Packard BioScience Co., Meriden Conn.). If a radiolabeledexpression product binds to the target molecule, the radiolabel remainsin proximity to the scintillant long enough to produce a detectablesignal.

In contrast, the labeled proteins that do not bind to the targetmolecule, or bind only briefly, will not remain near the scintillantlong enough to produce a signal above background. Any time spent nearthe scintillant caused by random Brownian motion will also not result ina significant amount of signal. Likewise, residual unincorporatedradiolabel used during the expression step may be present, but will notgenerate significant signal because it will be in solution rather thaninteracting with the target molecule. These non-binding interactionswill therefore cause a certain level of background signal that can bemathematically removed. If too many signals are obtained, salt or othermodifiers can be added directly to the assay plates until the desiredspecificity is obtained (Nichols et al., (1998) Anal. Biochem.257:112-119).

IV. Kinase Activity Assays

A number of different assays for kinase activity can be utilized forassaying for active modulators and/or determining specificity of amodulator for a particular kinase or group or kinases. In addition tothe assay mentioned in the Examples below, one of ordinary skill in theart will know of other assays that can be utilized and can modify anassay for a particular application. For example, numerous papersconcerning kinases described assays that can be used.

Additional alternative assays can employ binding determinations. Forexample, this sort of assay can be formatted either in a fluorescenceresonance energy transfer (FRET) format, or using an AlphaScreen(amplified luminescent proximity homogeneous assay) format by varyingthe donor and acceptor reagents that are attached to streptavidin or thephospho-specific antibody.

V. Organic Synthetic Techniques

A wide array of organic synthetic techniques exist in the art to meetthe challenge of constructing potential modulators. Many of theseorganic synthetic methods are described in detail in standard referencesources utilized by those skilled in the art. One example of suh areference is March, 1994, Advanced Organic Chemistry; Reactions,Mechanisms and Structure, New York, McGraw Hill. Thus, the techniquesuseful to synthesize a potential modulator of kinase function arereadily available to those skilled in the art of organic chemicalsynthesis.

Regarding the synthetic examples described herein, solvents includepolar and non-polar solvents known to those of skill in the art,including polar aprotic and polar protic solvents. Polar solventsinclude, without limitation, protic solvents such as methanol, ethanol,isopropyl alcohol, t-butanol, n-butanol, acetic acid, formic acid orwater, or aprotic solvents such as tetrahydrofuran (THF), acetonitrile,dioxane, methylene chloride, dimethylsulfoxide (DMSO), acetone,N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), ethyl acetate,1,2-dimethoxyethane, 1,2-dichloroethane, chloroform, 1,2-dichloroethane,or pyridine. Polar solvents include a mixture of water with any of theabove, or a mixture of any two or more of the above. Apolar solventsinclude, without limitation, toluene, benzene, chlorobenzene, xylenesand hexanes.

Regarding the synthetic examples described herein, reducing agentincludes, without limitation, a reducing agent such as catalyticreducing agents using hydrogen and transition metal catalysts such aspalladium, platinum, rhodium, etc. (e.g. Pt/acetic acid/H₂); a mixtureof trifluoroacetic acid and triethylsilane, borane tetrahydrofurancomplex, diborane, borane dimethylsulfide complex, and a combination ofsodium borohydride and boron trifluoride; metals such as reduced iron,zinc powder, magnesium etc.; metal hydrogen complex compounds such asalkali metal borohydrides (for example, potassium borohydride, sodiumborohydride, lithium borohydride, zinc borohydride, sodiumtriacetoxyborohydride, etc.), aluminum lithium hydride, etc.; metalhydrides such as sodium hydride, etc.; organic tin compounds(triphenyltin hydride, etc.); and metal salts such as nickel compounds,zinc compounds, tin compounds (for example tin(II) chloride), andsamarium iodide/pivalic acid/hexamethylphorphoric triamide.

Regarding the synthetic examples described herein, oxidizing agentincludes, without limitation, an oxidizing agent such as Dess-Martinreagent, TEMPO (2,2,6,6-tetramethylpiperidine-N-oxide), DDQ(2,3-Dichloro-5,6-dicyano-1,4-benzoquinone), PDC (pyridiniumdichromate), PCC (pyridinium chlorochromate), Pyridine.SO3, Chromiumtrioxide, p-nitroperbenzoic acid, magnesium monoperoxyphthalate, sodiumperiodate, potassium periodate, hydrogen peroxide, urea peroxide, alkalimetal bromates, cumene hydroperoxide, tert-butyl peroxide, peracids suchas performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoicacid, m-chloroperbenzoic acid, o-carboxyperbenzoic acid and the like;sodium metaperiodate, bichromic acid; bichromates such as sodiumbichromate, potassium bichromate; permanganic acid; permanganates suchas potassium permanganate, sodium permanganate; and lead salts such aslead tetraacetate.

VI. Alternative Compound Forms or Derivatives

(a) Isomers, Prodrugs, and Active Metabolites

Compounds contemplated herein are described with reference to bothgeneric formulae and specific compounds. In addition, the inventioncompounds may exist in a number of different forms or derivatives, allwithin the scope of the present invention. These include, for example,tautomers, stereoisomers, racemic mixtures, regioisomers, salts,prodrugs (e.g. carboxylic acid esters), solvated forms, differentcrystal forms or polymorphs, and active metabolites.

(b) Tautomers, Stereoisomers, Regioisomers, and Solvated Forms

It is understood that some compounds may exhibit tautomerism. In suchcases, the formulae provided herein expressly depict only one of thepossible tautomeric forms. It is therefore to be understood that theformulae provided herein are intended to represent any tautomeric formof the depicted compounds and are not to be limited merely to thespecific tautomeric form depicted by the drawings of the formulae.

Likewise, some of the compounds according to the present invention mayexist as stereoisomers, i.e. having the same atomic connectivity ofcovalently bonded atoms yet differing in the spatial orientation of theatoms. For example, compounds may be optical stereoisomers, whichcontain one or more chiral centers, and therefore, may exist in two ormore stereoisomeric forms (e.g. enantiomers or diastereomers). Thus,such compounds may be present as single stereoisomers (i.e., essentiallyfree of other stereoisomers), racemates, and/or mixtures of enantiomersand/or diastereomers. As another example, stereoisomers includegeometric isomers, such as cis- or trans-orientation of substituents onadjacent carbons of a double bond. All such single stereoisomers,racemates and mixtures thereof are intended to be within the scope ofthe present invention. Unless specified to the contrary, all suchsteroisomeric forms are included within the formulae provided herein.

In some embodiments, a chiral compound of the present invention is in aform that contains at least 80% of a single isomer (60% enantiomericexcess (“e.e.”) or diastereomeric excess (“d.e.”)), or at least 85% (70%e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5%(95% e.e. or d.e.), or 99% (98% e.e. or d.e.). As generally understoodby those skilled in the art, an optically pure compound having onechiral center is one that consists essentially of one of the twopossible enantiomers (i.e., is enantiomerically pure), and an opticallypure compound having more than one chiral center is one that is bothdiastereomerically pure and enantiomerically pure. In some embodiments,the compound is present in optically pure form.

For compounds in which synthesis involves addition of a single group ata double bond, particularly a carbon-carbon double bond, the additionmay occur at either of the double bond-linked atoms. For such compounds,the present invention includes both such regioisomers.

Additionally, the formulae are intended to cover solvated as well asunsolvated forms of the identified structures. For example, theindicated structures include both hydrated and non-hydrated forms. Otherexamples of solvates include the structures in combination with asuitable solvent such as isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, or ethanolamine.

(c) Prodrugs and Metabolites

In addition to the present formulae and compounds described herein, theinvention also includes prodrugs (generally pharmaceutically acceptableprodrugs), active metabolic derivatives (active metabolites), and theirpharmaceutically acceptable salts.

Prodrugs are compounds or pharmaceutically acceptable salts thereofwhich, when metabolized under physiological conditions or when convertedby solvolysis, yield the desired active compound. Prodrugs include,without limitation, esters, amides, carbamates, carbonates, ureides,solvates, or hydrates of the active compound. Typically, the prodrug isinactive, or less active than the active compound, but may provide oneor more of advantageous handling, administration, and/or metabolicproperties. For example, some prodrugs are esters of the activecompound; during metabolysis, the ester group is cleaved to yield theactive drug. Also, some prodrugs are activated enzymatically to yieldthe active compound, or a compound which, upon further chemicalreaction, yields the active compound.

In this context, a common example of a prodrug is an alkyl ester of acarboxylic acid. Relative to compounds of Formula I, Formula Ia, FormulaIb, Formula Ig, Formula II, Formula IIa, Formula IIb, Formula IIc,Formula IId, Formula IIe, Formula IIf, Formula IIg, Formula IIh, FormulaIII, Formula IIj, Formula IIk, Formula IIm, Formula IIn, Formula IIo,Formula IIp, or Formula III, further examples include, withoutlimitation, an amide or carbamate derivative at the pyrrole nitrogen(i.e. Ni) of the azaindole core.

As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed.Wermuth, Academic Press, San Diego, Calif., 2001), prodrugs can beconceptually divided into two non-exclusive categories, bioprecursorprodrugs and carrier prodrugs. Generally, bioprecursor prodrugs arecompounds that are inactive or have low activity compared to thecorresponding active drug compound, that contain one or more protectivegroups and are converted to an active form by metabolism or solvolysis.Both the active drug form and any released metabolic products shouldhave acceptably low toxicity. Typically, the formation of active drugcompound involves a metabolic process or reaction that is one of thefollow types:

Oxidative Reactions:

Oxidative reactions are exemplified without limitation to reactions suchas oxidation of alcohol, carbonyl, and acid functionalities,hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbonatoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbondouble bonds, oxidation of nitrogen-containing functional groups,oxidation of silicon, phosphorus, arsenic, and sulfur, oxidativeN-dealkylation, oxidative O- and S-dealkylation, oxidative deamination,as well as other oxidative reactions.

Reductive Reactions:

Reductive reactions are exemplified without limitation to reactions suchas reduction of carbonyl functionalities, reduction of alcoholfunctionalities and carbon-carbon double bonds, reduction ofnitrogen-containing functional groups, and other reduction reactions.

Reactions without Change in the Oxidation State:

Reactions without change in the state of oxidation are exemplifiedwithout limitation to reactions such as hydrolysis of esters and ethers,hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavageof non-aromatic heterocycles, hydration and dehydration at multiplebonds, new atomic linkages resulting from dehydration reactions,hydrolytic dehalogenation, removal of hydrogen halide molecule, andother such reactions.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improves uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, the prodrug and anyrelease transport moiety are acceptably non-toxic. For prodrugs wherethe transport moiety is intended to enhance uptake, typically therelease of the transport moiety should be rapid. In other cases, it isdesirable to utilize a moiety that provides slow release, e.g., certainpolymers or other moieties, such as cyclodextrins. (See, e.g., Cheng etal., U.S. Patent Publ. No. 2004/0077595, application Ser. No.10/656,838, incorporated herein by reference.) Such carrier prodrugs areoften advantageous for orally administered drugs. Carrier prodrugs can,for example, be used to improve one or more of the following properties:increased lipophilicity, increased duration of pharmacological effects,increased site-specificity, decreased toxicity and adverse reactions,and/or improvement in drug formulation (e.g. stability, watersolubility, suppression of an undesirable organoleptic or physiochemicalproperty). For example, lipophilicity can be increased by esterificationof hydroxyl groups with lipophilic carboxylic acids, or of carboxylicacid groups with alcohols, e.g., aliphatic alcohols. Wermuth, supra.

Prodrugs may proceed from prodrug form to active form in a single stepor may have one or more intermediate forms which may themselves haveactivity or may be inactive.

Metabolites, e.g., active metabolites, overlap with prodrugs asdescribed above, e.g., bioprecursor prodrugs. Thus, such metabolites arepharmacologically active compounds or compounds that further metabolizeto pharmacologically active compounds that are derivatives resultingfrom metabolic process in the body of a subject. Of these, activemetabolites are such pharmacologically active derivative compounds. Forprodrugs, the prodrug compound is generally inactive or of loweractivity than the metabolic product. For active metabolites, the parentcompound may be either an active compound or may be an inactive prodrug.

Prodrugs and active metabolites may be identified using routinetechniques known in the art. See, e.g., Bertolini et al., 1997, J. Med.Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci 86(7):756-757;Bagshawe, 1995, Drug Dev. Res., 34:220-230; Wermuth, supra.

(d) Pharmaceutically Acceptable Salts

Compounds can be formulated as or be in the form of pharmaceuticallyacceptable salts. Contemplated pharmaceutically acceptable salt formsinclude, without limitation, mono, bis, tris, tetrakis, and so on.Pharmaceutically acceptable salts are non-toxic in the amounts andconcentrations at which they are administered. The preparation of suchsalts can facilitate the pharmacological use by altering the physicalcharacteristics of a compound without preventing it from exerting itsphysiological effect. Useful alterations in physical properties includelowering the melting point to facilitate transmucosal administration andincreasing the solubility to facilitate administering higherconcentrations of the drug.

Pharmaceutically acceptable salts include acid addition salts such asthose containing sulfate, chloride, hydrochloride, fumarate, maleate,phosphate, sulfamate, acetate, citrate, lactate, tartrate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts canbe obtained from acids such as hydrochloric acid, maleic acid, sulfuricacid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lacticacid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamicacid, fumaric acid, and quinic acid.

Pharmaceutically acceptable salts also include basic addition salts suchas those containing benzathine, chloroprocaine, choline, diethanolamine,ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine,aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium,alkylamine, and zinc, when acidic functional groups, such as carboxylicacid or phenol are present. For example, see Remington's PharmaceuticalSciences, 19^(th) ed., Mack Publishing Co., Easton, Pa., Vol. 2, p.1457, 1995. Such salts can be prepared using the appropriatecorresponding bases.

Pharmaceutically acceptable salts can be prepared by standardtechniques. For example, the free-base form of a compound can bedissolved in a suitable solvent, such as an aqueous or aqueous-alcoholsolution containing the appropriate acid and then isolated byevaporating the solution. In another example, a salt can be prepared byreacting the free base and acid in an organic solvent.

Thus, for example, if the particular compound is a base, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like, or with an organicacid, such as acetic acid, maleic acid, succinic acid, mandelic acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, a pyranosidyl acid, such as glucuronic acid orgalacturonic acid, an alpha-hydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

Similarly, if the particular compound is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide or alkaline earth metal hydroxide, or the like. Illustrativeexamples of suitable salts include organic salts derived from aminoacids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary,secondary, and tertiary amines, and cyclic amines, such ashydroxyethylpyrrolidine, piperidine, morpholine or piperazine, andinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum and lithium.

The pharmaceutically acceptable salt of the different compounds may bepresent as a complex. Examples of complexes include 8-chlorotheophyllinecomplex (analogous to, e.g., dimenhydrinate: diphenhydramine8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrininclusion complexes.

Unless specified to the contrary, specification of a compound hereinincludes pharmaceutically acceptable salts of such compound.

(e) Polymorphic Forms

In the case of agents that are solids, it is understood by those skilledin the art that the compounds and salts may exist in different crystalor polymorphic forms, all of which are intended to be within the scopeof the present invention and specified formulae.

VII. Administration

The methods and compounds will typically be used in therapy for humansubjects. However, they may also be used to treat similar or identicalindications in other animal subjects. In this context, the terms“subject,” “animal subject,” and the like refer to human and non-humanvertebrates, e.g. mammals, such as non-human primates, sports andcommercial animals, e.g., equines, bovines, porcines, ovines, rodents,and pets, e.g., canines and felines.

Suitable dosage forms, in part, depend upon the use or the route ofadministration, for example, oral, transdermal, transmucosal, inhalant,or by injection (parenteral). Such dosage forms should allow thecompound to reach target cells. Other factors are well known in the art,and include considerations such as toxicity and dosage forms that retardthe compound or composition from exerting its effects. Techniques andformulations generally may be found in The Science and Practice ofPharmacy, 21^(st) edition, Lippincott, Williams and Wilkins,Philadelphia, Pa., 2005 (hereby incorporated by reference herein).

Compounds of the present invention (i.e. Formula I, Formula Ia, FormulaIb, Formula Ig, Formula II, Formula IIa, Formula IIb, Formula IIc,Formula IId, Formula IIe, Formula IIf, Formula IIg, Formula IIh, FormulaIII, Formula IIj, Formula IIk, Formula IIm, Formula IIn, Formula IIo,Formula IIp, or Formula III, and all sub-embodiments disclosed herein)can be formulated as pharmaceutically acceptable salts.

Carriers or excipients can be used to produce compositions. The carriersor excipients can be chosen to facilitate administration of thecompound. Examples of carriers include calcium carbonate, calciumphosphate, various sugars such as lactose, glucose, or sucrose, or typesof starch, cellulose derivatives, gelatin, vegetable oils, polyethyleneglycols and physiologically compatible solvents. Examples ofphysiologically compatible solvents include sterile solutions of waterfor injection (WFI), saline solution, and dextrose.

The compounds can be administered by different routes includingintravenous, intraperitoneal, subcutaneous, intramuscular, oral,transmucosal, rectal, transdermal, or inhalant. In some embodiments,oral administration is preferred. For oral administration, for example,the compounds can be formulated into conventional oral dosage forms suchas capsules, tablets, and liquid preparations such as syrups, elixirs,and concentrated drops.

For inhalants, compounds of the invention may be formulated as drypowder or a suitable solution, suspension, or aerosol. Powders andsolutions may be formulated with suitable additives known in the art.For example, powders may include a suitable powder base such as lactoseor starch, and solutions may comprise propylene glycol, sterile water,ethanol, sodium chloride and other additives, such as acid, alkali andbuffer salts. Such solutions or suspensions may be administered byinhaling via spray, pump, atomizer, or nebulizer, and the like. Thecompounds of the invention may also be used in combination with otherinhaled therapies, for example corticosteroids such as fluticasonepropionate, beclomethasone dipropionate, triamcinolone acetonide,budesonide, and mometasone furoate; beta agonists such as albuterol,salmeterol, and formoterol; anticholinergic agents such as ipratropiumbromide or tiotropium; vasodilators such as treprostinal and iloprost;enzymes such as DNAase; therapeutic proteins; immunoglobulin antibodies;an oligonucleotide, such as single or double stranded DNA or RNA, siRNA;antibiotics such as tobramycin; muscarinic receptor antagonists;leukotriene antagonists; cytokine antagonists; protease inhibitors;cromolyn sodium; nedocril sodium; and sodium cromoglycate.

Pharmaceutical preparations for oral use can be obtained, for example,by combining the active compounds with solid excipients, optionallygrinding a resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain tablets ordragee cores. Suitable excipients are, in particular, fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations, for example, maize starch, wheat starch, rice starch,potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC),and/or polyvinylpyrrolidone (PVP: povidone). If desired, disintegratingagents may be added, such as the cross-linked polyvinylpyrrolidone,agar, or alginic acid, or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally contain,for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel,polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dye-stuffs orpigments may be added to the tablets or dragee coatings foridentification or to characterize different combinations of activecompound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin (“gelcaps”), as well as soft, sealed capsulesmade of gelatin, and a plasticizer, such as glycerol or sorbitol. Thepush-fit capsules can contain the active ingredients in admixture withfiller such as lactose, binders such as starches, and/or lubricants suchas talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols (PEGs). In addition, stabilizers may be added.

Alternatively, injection (parenteral administration) may be used, e.g.,intramuscular, intravenous, intraperitoneal, and/or subcutaneous. Forinjection, the compounds of the invention are formulated in sterileliquid solutions, preferably in physiologically compatible buffers orsolutions, such as saline solution, Hank's solution, or Ringer'ssolution. In addition, the compounds may be formulated in solid form andredissolved or suspended immediately prior to use. Lyophilized forms canalso be produced.

Administration can also be by transmucosal, topical, transdermal, orinhalant means. For transmucosal, topical or transdermal administration,penetrants appropriate to the barrier to be permeated are used in theformulation. Such penetrants are generally known in the art, andinclude, for example, for transmucosal administration, bile salts andfusidic acid derivatives. In addition, detergents may be used tofacilitate permeation. Transmucosal administration, for example, may bethrough nasal sprays or suppositories (rectal or vaginal).

The topical compositions of this invention are formulated preferably asoils, creams, lotions, ointments, and the like by choice of appropriatecarriers known in the art. Suitable carriers include vegetable ormineral oils, white petrolatum (white soft paraffin), branched chainfats or oils, animal fats and high molecular weight alcohol (greaterthan C₁₂). The preferred carriers are those in which the activeingredient is soluble. Emulsifiers, stabilizers, humectants andantioxidants may also be included as well as agents imparting color orfragrance, if desired. Creams for topical application are preferablyformulated from a mixture of mineral oil, self-emulsifying beeswax andwater in which mixture the active ingredient, dissolved in a smallamount solvent (e.g. an oil), is admixed. Additionally, administrationby transdermal means may comprise a transdermal patch or dressing suchas a bandage impregnated with an active ingredient and optionally one ormore carriers or diluents known in the art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen.

The amounts of various compounds to be administered can be determined bystandard procedures taking into account factors such as the compoundIC₅₀, the biological half-life of the compound, the age, size, andweight of the subject, and the indication being treated. The importanceof these and other factors are well known to those of ordinary skill inthe art. Generally, a dose will be between about 0.01 and 50 mg/kg,preferably 0.1 and 20 mg/kg of the subject being treated. Multiple dosesmay be used.

The compounds of the invention may also be used in combination withother therapies for treating the same disease. Such combination useincludes administration of the compounds and one or more othertherapeutics at different times, or co-administration of the compoundand one or more other therapies. In some embodiments, dosage may bemodified for one or more of the compounds of the invention or othertherapeutics used in combination, e.g., reduction in the amount dosedrelative to a compound or therapy used alone, by methods well known tothose of ordinary skill in the art.

It is understood that use in combination includes use with othertherapies, drugs, medical procedures etc., where the other therapy orprocedure may be administered at different times (e.g. within a shorttime, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within alonger time (e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) than acompound of the present invention, or at the same time as a compound ofthe invention. Use in combination also includes use with a therapy ormedical procedure that is administered once or infrequently, such assurgery, along with a compound of the invention administered within ashort time or longer time before or after the other therapy orprocedure. In some embodiments, the present invention provides fordelivery of compounds of the invention and one or more other drugtherapeutics delivered by a different route of administration or by thesame route of administration. The use in combination for any route ofadministration includes delivery of compounds of the invention and oneor more other drug therapeutics delivered by the same route ofadministration together in any formulation, including formulations wherethe two compounds are chemically linked in such a way that they maintaintheir therapeutic activity when administered. In one aspect, the otherdrug therapy may be co-administered with one or more compounds of theinvention. Use in combination by co-administration includesadministration of co-formulations or formulations of chemically joinedcompounds, or administration of two or more compounds in separateformulations within a short time of each other (e.g. within an hour, 2hours, 3 hours, up to 24 hours), administered by the same or differentroutes. Co-administration of separate formulations includesco-administration by delivery via one device, for example the sameinhalant device, the same syringe, etc., or administration from separatedevices within a short time of each other. Co-formulations of compoundsof the invention and one or more additional drug therapies delivered bythe same route includes preparation of the materials together such thatthey can be administered by one device, including the separate compoundscombined in one formulation, or compounds that are modified such thatthey are chemically joined, yet still maintain their biologicalactivity. Such chemically joined compounds may have a linkage that issubstantially maintained in vivo, or the linkage may break down in vivo,separating the two active components.

VIII. Manipulation of c-kit and c-fms

As the full-length coding sequence and amino acid sequence of c-kit andc-fms from various mammals including human is known, cloning,construction of recombinant c-kit and c-fins, production andpurification of recombinant protein, introduction of c-kit or c-fms intoother organisms, and other molecular biological manipulations of c-kitand c-fms are readily performed.

Techniques for the manipulation of nucleic acids, such as, e.g.,subcloning, labeling probes (e.g. random-primer labeling using Klenowpolymerase, nick translation, amplification), sequencing, hybridizationand the like are well disclosed in the scientific and patent literature,see, e.g., Sambrook, ed., Molecular Cloning: a Laboratory Manual (2nded.), Vols. 1-3, Cold Spring Harbor Laboratory, (1989); CurrentProtocols in Molecular Biology, Ausubel, ed. John Wiley & Sons, Inc.,New York (1997); Laboratory Techniques in Biochemistry and MolecularBiology: Hybridization With Nucleic Acid Probes, Part I. Theory andNucleic Acid Preparation, Tijssen, ed. Elsevier, N.Y. (1993).

Nucleic acid sequences can be amplified as necessary for further useusing amplification methods, such as PCR, isothermal methods, rollingcircle methods, etc., are well known to the skilled artisan. See, e.g.,Saiki, “Amplification of Genomic DNA” in PCR

Protocols, Innis et al., Eds., Academic Press, San Diego, Calif. 1990,pp 13-20; Wharam et al., Nucleic Acids Res. 2001 Jun. 1; 29(11):E54-E54;Hafner et al., Biotechniques 2001 April; 30(4):852-6, 858, 860 passim;Zhong et al., Biotechniques 2001 April; 30(4):852-6, 858, 860 passim.

Nucleic acids, vectors, capsids, polypeptides, and the like can beanalyzed and quantified by any of a number of general means well knownto those of skill in the art. These include, e.g., analyticalbiochemical methods such as NMR, spectrophotometry, radiography,electrophoresis, capillary electrophoresis, high performance liquidchromatography (HPLC), thin layer chromatography (TLC), andhyperdiffusion chromatography, various immunological methods, e.g. fluidor gel precipitin reactions, immunodiffusion, immuno-electrophoresis,radioimmunoassays (RIAs), enzyme-linked immunosorbent assays (ELISAs),immuno-fluorescent assays, Southern analysis, Northern analysis,dot-blot analysis, gel electrophoresis (e.g. SDS-PAGE), nucleic acid ortarget or signal amplification methods, radiolabeling, scintillationcounting, and affinity chromatography.

Obtaining and manipulating nucleic acids used to practice the methods ofthe invention can be performed by cloning from genomic samples, and, ifdesired, screening and re-cloning inserts isolated or amplified from,e.g., genomic clones or cDNA clones. Sources of nucleic acid used in themethods of the invention include genomic or cDNA libraries contained in,e.g., mammalian artificial chromosomes (MACs), see, e.g., U.S. Pat. Nos.5,721,118; 6,025,155; human artificial chromosomes, see, e.g., Rosenfeld(1997) Nat. Genet. 15:333-335; yeast artificial chromosomes (YAC);bacterial artificial chromosomes (BAC); P1 artificial chromosomes, see,e.g., Woon (1998) Genomics 50:306-316; P1-derived vectors (PACs), see,e.g., Kern (1997) Biotechniques 23:120-124; cosmids, recombinantviruses, phages or plasmids.

The nucleic acids used to practice the methods of the invention can beoperatively linked to a promoter. A promoter can be one motif or anarray of nucleic acid control sequences which direct transcription of anucleic acid. A promoter can include necessary nucleic acid sequencesnear the start site of transcription, such as, in the case of apolymerase II type promoter, a TATA element. A promoter also optionallyincludes distal enhancer or repressor elements which can be located asmuch as several thousand base pairs from the start site oftranscription. A “constitutive” promoter is a promoter which is activeunder most environmental and developmental conditions. An “inducible”promoter is a promoter which is under environmental or developmentalregulation. A “tissue specific” promoter is active in certain tissuetypes of an organism, but not in other tissue types from the sameorganism. The term “operably linked” refers to a functional linkagebetween a nucleic acid expression control sequence (such as a promoter,or array of transcription factor binding sites) and a second nucleicacid sequence, wherein the expression control sequence directstranscription of the nucleic acid corresponding to the second sequence.

The nucleic acids used to practice the methods of the invention can alsobe provided in expression vectors and cloning vehicles, e.g., sequencesencoding the polypeptides used to practice the methods of the invention.Expression vectors and cloning vehicles used to practice the methods ofthe invention can comprise viral particles, baculovirus, phage,plasmids, phagemids, cosmids, fosmids, bacterial artificial chromosomes,viral DNA (e.g. vaccinia, adenovirus, foul pox virus, pseudorabies andderivatives of SV40), P1-based artificial chromosomes, yeast plasmids,yeast artificial chromosomes, and any other vectors specific forspecific hosts of interest (such as bacillus, Aspergillus and yeast).Vectors used to practice the methods of the invention can includechromosomal, non-chromosomal and synthetic DNA sequences. Large numbersof suitable vectors are known to those of skill in the art, and arecommercially available.

The nucleic acids used to practice the methods of the invention can becloned, if desired, into any of a variety of vectors using routinemolecular biological methods; methods for cloning in vitro amplifiednucleic acids are disclosed, e.g., U.S. Pat. No. 5,426,039. Tofacilitate cloning of amplified sequences, restriction enzyme sites canbe “built into” a PCR primer pair. Vectors may be introduced into agenome or into the cytoplasm or a nucleus of a cell and expressed by avariety of conventional techniques, well described in the scientific andpatent literature. See, e.g., Roberts (1987) Nature 328:731; Schneider(1995) Protein Expr. Purif. 6435:10; Sambrook, Tijssen or Ausubel. Thevectors can be isolated from natural sources, obtained from such sourcesas ATCC or GenBank libraries, or prepared by synthetic or recombinantmethods. For example, the nucleic acids used to practice the methods ofthe invention can be expressed in expression cassettes, vectors orviruses which are stably or transiently expressed in cells (e.g.episomal expression systems). Selection markers can be incorporated intoexpression cassettes and vectors to confer a selectable phenotype ontransformed cells and sequences. For example, selection markers can codefor episomal maintenance and replication such that integration into thehost genome is not required.

In one aspect, the nucleic acids used to practice the methods of theinvention are administered in vivo for in situ expression of thepeptides or polypeptides used to practice the methods of the invention.The nucleic acids can be administered as “naked DNA” (see, e.g., U.S.Pat. No. 5,580,859) or in the form of an expression vector, e.g., arecombinant virus. The nucleic acids can be administered by any route,including peri- or intra-tumorally, as described below. Vectorsadministered in vivo can be derived from viral genomes, includingrecombinantly modified enveloped or non-enveloped DNA and RNA viruses,preferably selected from baculoviridiae, parvoviridiae, picornoviridiae,herpesveridiae, poxyiridae, adenoviridiae, or picornnaviridiae. Chimericvectors may also be employed which exploit advantageous merits of eachof the parent vector properties (See e.g., Feng (1997) NatureBiotechnology 15:866-870). Such viral genomes may be modified byrecombinant DNA techniques to include the nucleic acids used to practicethe methods of the invention; and may be further engineered to bereplication deficient, conditionally replicating or replicationcompetent. In alternative aspects, vectors are derived from theadenoviral (e.g. replication incompetent vectors derived from the humanadenovirus genome, see, e.g., U.S. Pat. Nos. 6,096,718; 6,110,458;6,113,913; 5,631,236); adeno-associated viral and retroviral genomes.Retroviral vectors can include those based upon murine leukemia virus(MuLV), gibbon ape leukemia virus (GaLV), Simian Immuno deficiency virus(SIV), human immuno deficiency virus (HIV), and combinations thereof;see, e.g., U.S. Pat. Nos. 6,117,681; 6,107,478; 5,658,775; 5,449,614;Buchscher (1992) J. Virol. 66:2731-2739; Johann (1992) J. Virol.66:1635-1640). Adeno-associated virus (AAV)-based vectors can be used totransduce cells with target nucleic acids, e.g., in the in vitroproduction of nucleic acids and peptides, and in in vivo and ex vivogene therapy procedures; see, e.g., U.S. Pat. Nos. 6,110,456; 5,474,935;Okada (1996) Gene Ther. 3:957-964.

The present invention also relates to use of fusion proteins, andnucleic acids encoding them. A polypeptide used to practice the methodsof the invention can be fused to a heterologous peptide or polypeptide,such as N-terminal identification peptides which impart desiredcharacteristics, such as increased stability or simplified purification.Peptides and polypeptides used to practice the methods of the inventioncan also be synthesized and expressed as fusion proteins with one ormore additional domains linked thereto for, e.g., producing a moreimmunogenic peptide, to more readily isolate a recombinantly synthesizedpeptide, to identify and isolate antibodies and antibody-expressing Bcells, and the like. Detection and purification facilitating domainsinclude, e.g., metal chelating peptides such as polyhistidine tracts andhistidine-tryptophan modules that allow purification on immobilizedmetals, protein A domains that allow purification on immobilizedimmunoglobulin, and the domain utilized in the FLAGS extension/affinitypurification system (Immunex Corp, Seattle Wash.). The inclusion of acleavable linker sequences such as Factor Xa or enterokinase(Invitrogen, San Diego Calif.) between a purification domain and themotif-comprising peptide or polypeptide to facilitate purification. Forexample, an expression vector can include an epitope-encoding nucleicacid sequence linked to six histidine residues followed by a thioredoxinand an enterokinase cleavage site (see e.g., Williams (1995)Biochemistry 34:1787-1797; Dobeli (1998) Protein Expr. Purif.12:404-414). The histidine residues facilitate detection andpurification while the enterokinase cleavage site provides a means forpurifying the epitope from the remainder of the fusion protein. In oneaspect, a nucleic acid encoding a polypeptide used to practice themethods of the invention is assembled in appropriate phase with a leadersequence capable of directing secretion of the translated polypeptide orfragment thereof. Technology pertaining to vectors encoding fusionproteins and application of fusion proteins are well disclosed in thescientific and patent literature, see e.g., Kroll (1993) DNA Cell. Biol.12:441-53.

The nucleic acids and polypeptides used to practice the methods of theinvention can be bound to a solid support, e.g., for use in screeningand diagnostic methods. Solid supports can include, e.g., membranes(e.g. nitrocellulose or nylon), a microtiter dish (e.g. PVC,polypropylene, or polystyrene), a test tube (glass or plastic), a dipstick (e.g. glass, PVC, polypropylene, polystyrene, latex and the like),a microfuge tube, or a glass, silica, plastic, metallic or polymer beador other substrate such as paper. One solid support uses a metal (e.g.cobalt or nickel)-comprising column which binds with specificity to ahistidine tag engineered onto a peptide.

Adhesion of molecules to a solid support can be direct (i.e., themolecule contacts the solid support) or indirect (a “linker” is bound tothe support and the molecule of interest binds to this linker).Molecules can be immobilized either covalently (e.g. utilizing singlereactive thiol groups of cysteine residues (see, e.g., Colliuod (1993)Bioconjugate Chem. 4:528-536) or non-covalently but specifically (e.g.via immobilized antibodies (see, e.g., Schuhmann (1991) Adv. Mater.3:388-391; Lu (1995) Anal. Chem. 67:83-87; the biotin/strepavidin system(see, e.g., Iwane (1997) Biophys. Biochem. Res. Comm. 230:76-80); metalchelating, e.g., Langmuir-Blodgett films (see, e.g., Ng (1995) Langmuir11:4048-55); metal-chelating self-assembled monolayers (see, e.g., Sigal(1996) Anal. Chem. 68:490-497) for binding of polyhistidine fusions.

Indirect binding can be achieved using a variety of linkers which arecommercially available. The reactive ends can be any of a variety offunctionalities including, but not limited to: amino reacting ends suchas N-hydroxysuccinimide (NHS) active esters, imidoesters, aldehydes,epoxides, sulfonyl halides, isocyanate, isothiocyanate, and nitroarylhalides; and thiol reacting ends such as pyridyl disulfides, maleimides,thiophthalimides, and active halogens. The heterobifunctionalcrosslinking reagents have two different reactive ends, e.g., anamino-reactive end and a thiol-reactive end, while homobifunctionalreagents have two similar reactive ends, e.g., bismaleimidohexane (BMH)which permits the cross-linking of sulfhydryl-containing compounds. Thespacer can be of varying length and be aliphatic or aromatic. Examplesof commercially available homobifunctional cross-linking reagentsinclude, but are not limited to, the imidoesters such as dimethyladipimidate dihydrochloride (DMA); dimethyl pimelimidate dihydrochloride(DMP); and dimethyl suberimidate dihydrochloride (DMS).Heterobifunctional reagents include commercially available activehalogen-NHS active esters coupling agents such as N-succinimidylbromoacetate and N-succinimidyl (4-iodoacetyl)aminobenzoate (SIAB) andthe sulfosuccinimidyl derivatives such assulfosuccinimidyl(4-iodoacetyl)aminobenzoate (sulfo-SIAB) (Pierce).Another group of coupling agents is the heterobifunctional and thiolcleavable agents such as N-succinimidyl 3-(2-pyridyldithio)propionate(SPDP) (Pierce Chemicals, Rockford, Ill.).

Antibodies can also be used for binding polypeptides and peptides usedto practice the methods of the invention to a solid support. This can bedone directly by binding peptide-specific antibodies to the column or itcan be done by creating fusion protein chimeras comprisingmotif-containing peptides linked to, e.g., a known epitope (e.g. a tag(e.g. FLAG, myc) or an appropriate immunoglobulin constant domainsequence (an “immunoadhesin,” see, e.g., Capon (1989) Nature 377:525-531(1989).

Nucleic acids or polypeptides used to practice the methods of theinvention can be immobilized to or applied to an array. Arrays can beused to screen for or monitor libraries of compositions (e.g. smallmolecules, antibodies, nucleic acids, etc.) for their ability to bind toor modulate the activity of a nucleic acid or a polypeptide used topractice the methods of the invention. For example, in one aspect of theinvention, a monitored parameter is transcript expression of a genecomprising a nucleic acid used to practice the methods of the invention.One or more, or all the transcripts of a cell can be measured byhybridization of a sample comprising transcripts of the cell, or nucleicacids representative of or complementary to transcripts of a cell, byhybridization to immobilized nucleic acids on an array, or “biochip.” Byusing an “array” of nucleic acids on a microchip, some or all of thetranscripts of a cell can be simultaneously quantified. Alternatively,arrays comprising genomic nucleic acid can also be used to determine thegenotype of a newly engineered strain made by the methods of theinvention. Polypeptide arrays” can also be used to simultaneouslyquantify a plurality of proteins.

The terms “array” or “microarray” or “biochip” or “chip” as used hereinis a plurality of target elements, each target element comprising adefined amount of one or more polypeptides (including antibodies) ornucleic acids immobilized onto a defined area of a substrate surface. Inpracticing the methods of the invention, any known array and/or methodof making and using arrays can be incorporated in whole or in part, orvariations thereof, as disclosed, for example, in U.S. Pat. Nos.6,277,628; 6,277,489; 6,261,776; 6,258,606; 6,054,270; 6,048,695;6,045,996; 6,022,963; 6,013,440; 5,965,452; 5,959,098; 5,856,174;5,830,645; 5,770,456; 5,632,957; 5,556,752; 5,143,854; 5,807,522;5,800,992; 5,744,305; 5,700,637; 5,556,752; 5,434,049; see also, e.g.,WO 99/51773; WO 99/09217; WO 97/46313; WO 96/17958; see also, e.g.,Johnston (1998) Curr. Biol. 8:R171-R174; Schummer (1997) Biotechniques23:1087-1092; Kern (1997) Biotechniques 23:120-124; Solinas-Toldo (1997)Genes, Chromosomes & Cancer 20:399-407; Bowtell (1999) Nature GeneticsSupp. 21:25-32. See also published U.S. patent application Nos.20010018642; 20010019827; 20010016322; 20010014449; 20010014448;20010012537; 20010008765.

Host Cells and Transformed Cells

The invention also provides a transformed cell comprising a nucleic acidsequence used to practice the methods of the invention, e.g., a sequenceencoding a polypeptide used to practice the methods of the invention, ora vector used to practice the methods of the invention. The host cellmay be any of the host cells familiar to those skilled in the art,including prokaryotic cells, eukaryotic cells, such as bacterial cells,fungal cells, yeast cells, mammalian cells, insect cells, or plantcells. Exemplary bacterial cells include E. coli, Streptomyces, Bacillussubtilis, Salmonella typhimurium and various species within the generaPseudomonas, Streptomyces, and Staphylococcus. Exemplary insect cellsinclude Drosophila S2 and Spodoptera Sf9. Exemplary animal cells includeCHO, COS or Bowes melanoma or any mouse or human cell line. Theselection of an appropriate host is within the abilities of thoseskilled in the art.

Vectors may be introduced into the host cells using any of a variety oftechniques, including transformation, transfection, transduction, viralinfection, gene guns, or Ti-mediated gene transfer. Particular methodsinclude calcium phosphate transfection, DEAE-Dextran mediatedtransfection, lipofection, or electroporation.

Engineered host cells can be cultured in conventional nutrient mediamodified as appropriate for activating promoters, selectingtransformants or amplifying the genes used to practice the methods ofthe invention. Following transformation of a suitable host strain andgrowth of the host strain to an appropriate cell density, the selectedpromoter may be induced by appropriate means (e.g. temperature shift orchemical induction) and the cells may be cultured for an additionalperiod to allow them to produce the desired polypeptide or fragmentthereof.

Cells can be harvested by centrifugation, disrupted by physical orchemical means, and the resulting crude extract is retained for furtherpurification. Microbial cells employed for expression of proteins can bedisrupted by any convenient method, including freeze-thaw cycling,sonication, mechanical disruption, or use of cell lysing agents. Suchmethods are well known to those skilled in the art. The expressedpolypeptide or fragment can be recovered and purified from recombinantcell cultures by methods including ammonium sulfate or ethanolprecipitation, acid extraction, anion or cation exchange chromatography,phosphocellulose chromatography, hydrophobic interaction chromatography,affinity chromatography, hydroxylapatite chromatography and lectinchromatography. Protein refolding steps can be used, as necessary, incompleting configuration of the polypeptide. If desired, highperformance liquid chromatography (HPLC) can be employed for finalpurification steps.

Various mammalian cell culture systems can also be employed to expressrecombinant protein. Examples of mammalian expression systems includethe COS-7 lines of monkey kidney fibroblasts and other cell linescapable of expressing proteins from a compatible vector, such as theC127, 3T3, CHO, HeLa and BHK cell lines.

The constructs in host cells can be used in a conventional manner toproduce the gene product encoded by the recombinant sequence. Dependingupon the host employed in a recombinant production procedure, thepolypeptides produced by host cells containing the vector may beglycosylated or may be non-glycosylated. Polypeptides used to practicethe methods of the invention may or may not also include an initialmethionine amino acid residue.

Cell-free translation systems can also be employed to produce apolypeptide used to practice the methods of the invention. Cell-freetranslation systems can use mRNAs transcribed from a DNA constructcomprising a promoter operably linked to a nucleic acid encoding thepolypeptide or fragment thereof. In some aspects, the DNA construct maybe linearized prior to conducting an in vitro transcription reaction.The transcribed mRNA is then incubated with an appropriate cell-freetranslation extract, such as a rabbit reticulocyte extract, to producethe desired polypeptide or fragment thereof.

The expression vectors can contain one or more selectable marker genesto provide a phenotypic trait for selection of transformed host cellssuch as dihydrofolate reductase or neomycin resistance for eukaryoticcell culture, or such as tetracycline or ampicillin resistance in E.coli.

For transient expression in mammalian cells, cDNA encoding a polypeptideof interest may be incorporated into a mammalian expression vector, e.g.pcDNA1, which is available commercially from Invitrogen Corporation (SanDiego, Calif., U.S.A.; catalogue number V490-20). This is amultifunctional 4.2 kb plasmid vector designed for cDNA expression ineukaryotic systems, and cDNA analysis in prokaryotes, incorporated onthe vector are the CMV promoter and enhancer, splice segment andpolyadenylation signal, an SV40 and Polyoma virus origin of replication,and M13 origin to rescue single strand DNA for sequencing andmutagenesis, Sp6 and T7 RNA promoters for the production of sense andanti-sense RNA transcripts and a Col E1-like high copy plasmid origin. Apolylinker is located appropriately downstream of the CMV promoter (and3′ of the T7 promoter).

The cDNA insert may be first released from the above phagemidincorporated at appropriate restriction sites in the pcDNAI polylinker.Sequencing across the junctions may be performed to confirm properinsert orientation in pcDNAI. The resulting plasmid may then beintroduced for transient expression into a selected mammalian cell host,for example, the monkey-derived, fibroblast like cells of the COS-1lineage (available from the American Type Culture Collection, Rockville,Md. as ATCC CRL 1650).

For transient expression of the protein-encoding DNA, for example, COS-1cells may be transfected with approximately 8 μg DNA per 10⁶ COS cells,by DEAE-mediated DNA transfection and treated with chloroquine accordingto the procedures described by Sambrook et al, Molecular Cloning: ALaboratory Manual, 1989, Cold Spring Harbor Laboratory Press, ColdSpring Harbor N.Y., pp. 16.30-16.37. An exemplary method is as follows.Briefly, COS-1 cells are plated at a density of 5×10⁶ cells/dish andthen grown for 24 hours in FBS-supplemented DMEM/F12 medium. Medium isthen removed and cells are washed in PBS and then in medium. Atransfection solution containing DEAE dextran (0.4 mg/ml), 100 μMchloroquine, 10% NuSerum, DNA (0.4 mg/ml) in DMEM/F12 medium is thenapplied on the cells 10 ml volume. After incubation for 3 hours at 37°C., cells are washed in PBS and medium as just described and thenshocked for 1 minute with 10% DMSO in DMEM/F12 medium. Cells are allowedto grow for 2-3 days in 10% FBS-supplemented medium, and at the end ofincubation dishes are placed on ice, washed with ice cold PBS and thenremoved by scraping. Cells are then harvested by centrifugation at 1000rpm for 10 minutes and the cellular pellet is frozen in liquid nitrogen,for subsequent use in protein expression. Northern blot analysis of athawed aliquot of frozen cells may be used to confirm expression ofreceptor-encoding cDNA in cells under storage.

In a like manner, stably transfected cell lines can also prepared, forexample, using two different cell types as host: CHO K1 and CHO Pro5. Toconstruct these cell lines, cDNA coding for the relevant protein may beincorporated into the mammalian expression vector pRC/CMV (Invitrogen),which enables stable expression. Insertion at this site places the cDNAunder the expression control of the cytomegalovirus promoter andupstream of the polyadenylation site and terminator of the bovine growthhormone gene, and into a vector background comprising the neomycinresistance gene (driven by the SV40 early promoter) as selectablemarker.

An exemplary protocol to introduce plasmids constructed as describedabove is as follows. The host CHO cells are first seeded at a density of5×10⁵ in 10% FBS-supplemented MEM medium. After growth for 24 hours,fresh medium is added to the plates and three hours later, the cells aretransfected using the calcium phosphate-DNA co-precipitation procedure(Sambrook et al, supra). Briefly, 3 μg of DNA is mixed and incubatedwith buffered calcium solution for 10 minutes at room temperature. Anequal volume of buffered phosphate solution is added and the suspensionis incubated for 15 minutes at room temperature. Next, the incubatedsuspension is applied to the cells for 4 hours, removed and cells wereshocked with medium containing 15% glycerol. Three minutes later, cellsare washed with medium and incubated for 24 hours at normal growthconditions. Cells resistant to neomycin are selected in 10%FBS-supplemented alpha-MEM medium containing G418 (1 mg/ml). Individualcolonies of G418-resistant cells are isolated about 2-3 weeks later,clonally selected and then propagated for assay purposes.

EXAMPLES

A number of examples illustrative of the present invention are describedbelow. In most cases, alternative techniques could also be used. Theexamples are intended to be illustrative and are not limiting orrestrictive to the scope of the invention. Unless specifically noted tothe contrary, in cases where a compound number is not preceeded by a“P-” (e.g., “P-0001”) in the Examples section, compound naming and/orenumeration is not related to naming and/or enumeration employed inother sections of this application. Similarly, structure and substituentnaming and enumeration within the Examples are independent of structureand substituent naming and enumeration in above sections of thisapplication unless clearly indicated otherwise.

In the following Examples, it is understood that the solvents andreagents used or suggested are not limiting, and can be substitutedappropriately with solvents and reagents known to those of skill in theart. Reaction products may be isolated by means known in the art, suchas extraction with a suitable solvent, precipitation from a suitablesolvent, chromatography using a suitable solvent system, includingsilica gel column chromatography, HPLC, preparative TLC, and the like.Exemplary methods for synthesis of compounds of the present inventionmay be found in US Patent Application Publication number US2007/0032519, the disclosure of which is hereby incorporated byreference. The 1H-pyrrolo[2,3-b]pyridine core of compounds described inthe examples may also be referred to as 7-azaindole in the examples.

Example 1 Synthesis of compound of Formula I, where X₁, X₂, Y₁ and Y₂are CH and L¹ is —CH₂—

Compounds of Formula I, as described in paragraph [0011], where X₁, X₂,Y₁ and Y₂ are CH and L¹ is —CH₂— or —CO— may be synthesized from7-azaindole according to one of the following Schemes 1-3, where R²⁴ isconsistent with Art, which can be further substituted to providecompounds where R²⁴ is Ar₁-L²-R¹ as described for Formula I.

Step-1—Synthesis of Compound 2.

Compound 2 is synthesized from commercially available 7-azaindolefollowing the literature procedure (Robinson, J. Am. Chem. Soc., 1955,77, p. 457).

Step-2—Synthesis of Compound of Formula II

Compound of Formula II, where P is a protecting group, is synthesized bydeprotonation using base (e.g. BuLi, NaH) in aprotic solvent liketetrahydrofuran or ether and reacting the anion with a silyl chloride(e.g. TIPS) or an anhydride (e.g. Boc anhydride). The compound isisolated by following standard procedure (quenching with ice-cold brine,work up, and purification by flash silica gel chromatography).

Steps-3 and 4—Synthesis of Compound of Formula 1

Compounds of Formula I, wherein R²⁴ is Ar₁ as defined in Formula I, issynthesized through the reaction of compounds of Formula II withisopropyl chloroformate (or ethyl chloroformate) at room temperature intoluene to give a 3-chloromethyl intermediate. This intermediate iscooled to −78° C. and immediately reacted with an organocopper reagent,which is generated from the reaction between a Grignard reagent (ororganolithium reagent) and a solution of copper cyanide and LiCl. Themixture is stirred at −78° C. for one hour and allowed to warm to roomtemperature. The reaction is quenched with a solution of 4:1 ammoniumchloride:ammonium hydroxide. The reaction is worked up in the usualmanner and purified by flash silica gel chromatography to give thenitrogen-protected compound. The final compound can be realized throughthe deprotection of the protecting group (Boc, TIPS) using standardconditions (TFA or NH₄F) at room temperature.

Step-1—Synthesis of Compound 3

Compound 3 is synthesized by reacting commercially available7-azaindole, compound 1, with hexamethyltetramine and acetic acid inwater with heating to reflux for two hours. After cooling, the desiredcompound is precipitated and collected by filtration.

Step-2—Synthesis of Compound of Formula III

Compound of Formula III, where P is a protecting group, is synthesizedby reacting compound 3 with an appropriate reagent to introduce aprotecting group (e.g. tert-butyloxycarbonyl di anhydride) and a base(e.g. sodium hydride) in an appropriate solvent (e.g. tetrahydrofuran)typically at room temperature for 12-18 hours. The compound can beisolated by conventional means (e.g. extraction).

Step-3—Synthesis of Compound of Formula IV

Compound of Formula IV, wherein R²⁴ is Art, is synthesized by reactingcompound of Formula III in an appropriate solvent (e.g.1,2-dimethoxyethane) with a Grignard reagent of the formula R²⁴MgCl orR²⁴MgBr (e.g. pyridinyl magnesium bromide) or an equivalent nucleophilein an appropriate solvent (e.g. tetrahydrofuran) under inert atmospherecooled typically to −10° C. The reaction is typically allowed to warm toroom temperature and stirred for 12-18 hours. The desired compound ispurified by reverse phase high pressure liquid chromatography.

Steps-4 and 5—Synthesis of an Intermediate of Compound of Formula I

An intermediate of compound of Formula I is synthesized by reactingcompound of Formula IV with a reducing agent (e.g. sodium borohydride)in a polar solvent (e.g. ethanol) typically with heating to 80° C. for1-4 hours. The reaction is quenched with the addition of methanol andconcentrated and purified by reverse phase high performance liquidchromatography. Compound of Formula I where R²⁴ is Ar₁ is synthesized byreacting this intermediate with an appropriate reagent to remove theprotecting group, P, (e.g. hydrochloric acid) in an apolar solvent (e.g.dioxane). The final compound is isolated by standard procedures (e.g.reverse phase preparative high pressure liquid chromatography).

Step-1—Synthesis of Compound of Formula I′

Compound of Formula I′ where R²⁴ is Art, is synthesized by reactingcompound 1 with an activating agent (e.g. methyl magnesium bromide andzinc dichloride or anhydrous aluminum chloride) and a heteroaryl acidchloride (e.g. nicotinic acid chloride) in a non-reactive solvent (e.g.dichloromethane), under inert atmosphere (e.g. argon), at roomtemperature or with heating up to reflux for 18-24 hours. The compoundis isolated by standard procedures (e.g. extraction and silica-gelchromatography).

Example 2 Synthesis of intermediate3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(6) and(3-(6-Bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine)(6a)

Compound 6, an intermediate to compounds of Formula I, as described inparagraph [0011], where X₁, X₂, Y₁ and Y₂ are CH, n is 1, P, Q and T areCH and L¹ is —CH₂—, may be synthesized in four steps from 7-azaindoleaccording to the following Scheme 4.

Step-1—Synthesis of dimethyl-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine(2)

Into a 3-neck round bottom flask was added Isopropyl alcohol (320.0 mL)followed by the addition of 1H-pyrrolo[2,3-b]pyridine 1 (7.10 g, 60.1mmol), dimethylamine hydrochloride (5.4 g, 0.066 mol), and formaldehyde(2.0 g, 0.066 mol). The reaction mixture was stirred at room temperaturefor 12 hours, and then refluxed for 30 minutes. The suspension solutionwas evaporated to dryness in vacuo. To the residue was added water (60.0mL, 3.33 mol) and concentrated hydrochloric acid (6.0 mL, 0.20 mol). Thewater layer was extracted with ether and the aqueous layer wasneutralized with potassium carbonate. The aqueous layer was extractedwith dichloromethane, dried over sodium sulfate and concentrated to givethe compound, which was then further washed with ether and dried toafford compound 2 (7.1 g, yield=67.4%), as a white solid.

Step-2—Synthesis of dimethyl-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine(4)

Into a round bottom flask 7-Azagramine 2 (5.38 g, 30.7 mmol),N,N-dimethylformamide (25.0 mL), and sodium hydride (1.35 g, 33.8 mol)were combined. Into the reaction was added triisopropylsilyl chloride(6.8 mL, 0.032 mol). The reaction was stirred at 20° C. for 12 hours.The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate, concentrated and purified with biotage to give compound 4 (6.0g, yield=58.8%) as a colorless oil.

Step-3—Synthesis of3-chloromethyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (5)

Into a round bottom flask was added compound 4 (500.0 mg, 1.51 mmol) andtoluene (5.0 mL, 0.047 mol) under an atmosphere of nitrogen. Into thereaction mixture 1.0 M isopropyl chloroformate in toluene (1.6 mL) wasadded slowly at room temperature. The reaction mixture was stirred foranother 2 hours to give desired compound 5 used for next step withoutpurification.

Step-4—Synthesis of3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(6)

Into a round bottom flask was added 5-iodo-2-chloro-pyridine (315.0 mg,1.32 mmol) and tetrahydrofuran (12.0 mL, 0.15 mol) at −40° C. under anatmosphere of nitrogen. Into the reaction 2.0 M of isopropylmagnesiumchloride in tetrahydrofuran (0.72 mL, 1.44 mmol) was added. The reactionmixture was stirred for 40 minutes at −40° C. TLC (hexane/ethyl acetate2:1) indicated no starting material. Into the reaction mixture 0.6 M ofCuCN.2LiCl in tetrahydrofuran (2.4 mL, 1.44 mmol) was added. Thereaction mixture was allowed to come to room temperature for 5 minutesand trimethyl phosphite (0.29 mL, 2.4 mmol) was added. After 10 minutes,this solution was added into a round bottom flask containing compound 5(315.0 mg) and toluene (8.0 mL). The reaction was stirred at 20° C. for40 hours. The reaction mixture was poured into water and the compoundextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate, concentrated and purified with biotage(dichloromethane/methanol 1:10) to give compound 6 (230 mg, yield=59.0%)as a white solid. Compound 6a(3-(6-Bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine)(MS (ESI) [M+H⁺]⁺=288.1, 290.1) was prepared substituting5-iodo-2-chloro-pyridine with 5-iodo-2-bromo-pyridine in Step 4, withreaction conditions and work up procedure the same as that for thesynthesis of compound 6.

Example 3 Synthesis of intermediate(6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (7)

Compound 7, an intermediate to compounds of Formula I, as described inparagraph [011], where X₁, X₂, Y₁ and Y₂ are CH, n is 1, P, Q and T areCH and L¹ is —CO—, may be synthesized in one step from 7-azaindoleaccording to the following Scheme 5.

Into a round bottom flask was added aluminum trichloride (16.0 g, 0.12mol) and dichloromethane (100.0 mL) under an atmosphere of nitrogen.Into the reaction mixture 1H-Pyrrolo[2,3-b]pyridine 1 (3.2 g, 0.027 mol)in dichloromethane (20.0 mL) was added. The reaction was stirred at roomtemperature for 70.0 minutes and 6-Chloropyridine-3-carbonyl chloride 8(5.4 g, 0.031 mol) in dichloromethane (10.0 mL) was added. The reactionmixture was stirred at room temperature for 3 hours. Methanol (10 mL)was added to the reaction mixture and the solvent was evaporated invacuo. The residue was poured into water and the precipitated compoundwas removed by filtration. The aqueous layer was extracted with ethylacetate and the organic layer was dried and concentrated and combinedwith the solid isolated by filtration to give 7 (6.2 g, yield=88.6%) asa white solid. MS (ESI) [M+H⁺]⁺=258.

Example 4 Synthesis ofbenzyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0001)

Benzyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0001) was prepared in two steps from3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(6) according to Scheme 6.

Step-1—Synthesis ofbenzyl-[5-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(10)

Into a round bottom flask was added3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine6 (160.0 mg, 0.40 mmol, prepared as described in Example 2), benzylamine(32, 0.1 mL, 0.90 mmol), palladium acetate (17.0 mg, 0.076 mmol),toluene (10.0 mL), potassium tert-butoxide (80.0 mg, 0.71 mmol) and2-(di-t-butylphosphino)biphenyl (31.4 mg, 0.11 mmol) under an atmosphereof nitrogen. The reaction was stirred under reflux for 3 hours. TLC andMS indicated no starting material. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, concentrated and purified withbiotage (dichloromethane/methanol 1:20) to give compound 10 (110 mg,yield=58.5%) as a white solid. MS (ESI) [M+H⁺]⁺=471.

Step-2—Synthesis ofbenzyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0001)

Into a round bottom flask was addedbenzyl-[5-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine10 (400.0 mg, 0.85 mmol), tetrahydrofuran (20.0 mL) andtetra-n-butylammonium fluoride (240 mg, 0.93 mmol). The reaction mixturewas stirred at 20° C. for 30 minutes. TLC indicated no startingmaterial. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, concentrated and purified with biotage(dichloromethane/methanol 1:10) to give compound P-0001 (220 mg,Yield=82.4%) as a white solid. MS (ESI) [M+H⁺]⁺=315.

Additional compounds were prepared following the protocol of Scheme 6,substituting benzyl amine with a suitable amine in Step 1, and usingeither3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine6 or3-(6-Bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine6a, in Step 1. The following compounds were made following thisprocedure:

-   Dimethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0021),-   (4-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0004),-   (4-chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0005),-   (4-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0006),-   (4-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0007), and-   [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-thiophen-2-ylmethyl-amine    (P-0008).

The following table indicates the amine used in Step 1 in place ofbenzyl amine in Column 3, and whether3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridineor3-(6-Bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridinewas used in Step 1 in Column 2 (Cl or Br, respectively), with thecompound structure in Column 4, experimental mass spectrometry result inColumn 5, and compound number in Column 1.

MS(ESI) Starting [M + H⁺]⁺ azaindole Amine Compound observed P-0021 Cl

253   P-0004 Br

344.4 P-0005 Br

348.8 P-0006 Br

332.4 P-0007 Br

328.4 P-0008 Br

330.4

Example 5 Synthesis of(6-Benzylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0002)

(6-Benzylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0002) was prepared in one step from(6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (7)according to Scheme 7.

Into a pressure tube was added(6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 7(270.0 mg, 1.05 mmol, prepared as described in Example 3), andbenzylamine (32, 0.7 mL, 0.006 mol) and tetrahydrofuran (25.0 mL) underan atmosphere of nitrogen. The reaction mixture was heated to 185° C.for 60 hours. The reaction mixture was concentrated to remove most ofthe solvent and the residue was poured into water and extracted withethyl acetate. The organic layer was dried over sodium sulfate,concentrated and purified with biotage (dichloromethane/methanol 1:20)to give compound P-0002 (30 mg, yield=8.7%) as a white solid. MS (ESI)[M+H⁺]=329.

Additional compounds were prepared following the protocol of Scheme 7,replacing benzylamine with a suitable amine. The following compoundswere made following this procedure:

-   [6-(4-Fluoro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-0015),-   [6-(3-Fluoro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-0016),-   (1H-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-methanone    (P-0017),-   (1H-Pyrrolo[2,3-b]pyridin-3-yl)-{6-[(thiophen-2-ylmethyl)-amino]-pyridin-3-yl}-methanone    (P-0018),-   (6-Phenylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-0023),-   (6-Isopropylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-0024),-   (6-Isobutylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-0025),-   [6-(3-Benzyloxy-phenylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-0026),-   [6-(Cyclopropylmethyl-amino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-0030),-   [6-(Cyclohexylmethyl-amino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-0031),

The following table indicates the amine substituted in place ofbenzylamine in column 2, to provide these compounds, shown by structurein column 3. Column 1 provides the compound number and column 4 givesthe experimental mass spectrometry result.

MS(ESI) [M + H⁺]⁺ Amine Compound observed P-0015

347.0 P-0016

347.1 P-0017

396.9 P-0018

335.0 P-0023

315.1 P-0024

279   [M − H⁺]⁻ P-0025

293   [M − H⁺]⁻ P-0026

419   [M − H⁺]⁻ P-0030

293.1 P-0031

335.2

Example 6 Synthesis ofIsobutyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0028

Compound P-0028 was synthesized in 1 step from6-Isobutylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0025 as shown in Scheme 8.

Step-1-Synthesis ofIsobutyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0028)

To(6-Isobutylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0025, 60.0 mg, 0.20 mmol, prepared as described in Example 5) in1,2-ethanediol (5.0 mL) was added hydrazine (1.0 mL, 0.032 mol) andpotassium hydroxide (200.0 mg, 3.56 mmol). The reaction mixture washeated to 180° C. overnight. The reaction mixture was poured into waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over sodium sulfate, concentrated and purified by silicagel column chromatography eluting with 10% methanol in dichloromethaneto give compound (P-0028, 10 mg, 16.7%). MS (ESI) [M+H⁺]⁺=281.

Cyclopropylmethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0032)

was prepared following the protocol of Scheme 8, substituting(6-Isobutylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0025 with[6-(Cyclopropylmethyl-amino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0030 (prepared as described in Example 5). MS (ESI) [M+H⁺]⁺=279.

Cyclohexylmethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0033)

was prepared following the protocol of Scheme 8, substituting(6-Isobutylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0025 with[6-(Cyclohexylmethyl-amino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0031, (prepared as described in Example 5). MS (ESI) [M+H⁺]⁺=321.

Example 7 3-(6-Isopropyl-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridineP-0019

3-(6-Isopropyl-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine P-0019 wassynthesized in 2 steps from3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine6 as shown in Scheme 9.

Step-1-Synthesis of3-(6-Isopropyl-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(39)

To3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(6, 54.0 mg, 0.000135 mol, prepared as described in Example 2) inTetrahydrofuran (4.0 mL) were added[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (23.0 mg)and Isopropylmagnesium Chloride (0.15 mL, 2.0 M in Tetrahydrofuran). Thereaction was stirred at 20° C. under an atmosphere of Nitrogen for 3hours. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, concentrated and purified by silica gel columnchromatography eluting with 10% methanol in dichloromethane to givecompound 39 (38 mg, 70.4%).

Step-2-Synthesis of3-(6-Isopropyl-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (P-0019)

To3-(6-Isopropyl-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(39, 35.0 mg, 0.086 mmol) in tetrahydrofuran (3.0 mL) was addedtetra-n-butylammonium fluoride (29 mg, 0.11 mmol). The reaction wasstirred at 20° C. for 30 minutes. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, concentrated and purified bysilica gel column chromatography eluting with 10% methanol indichloromethane to give compound (P-0019, 18.0 mg, 81.9%). MS (ESI)[M+H⁺]⁺=252.

Example 8 Synthesis of[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine(P-0003)

[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine(P-0003) was prepared in three steps from(6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (7)according to Scheme 10.

Step-1—Synthesis of(1H-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-methanone(P-0017)

Into a pressure flask was added(6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 7 (3.5g, 0.014 mol, prepared as described in Example 3),4-(trifluoromethyl)benzylamine (30, 9.0 g, 0.051 mol), tetrahydrofuran(30.0 mL, 0.37 mol), palladium acetate (200.0 mg, 0.890 mmol) and2-(di-t-butylphosphino)biphenyl (200.0 mg, 0.67 mmol). The reactionmixture was stirred at 180° C. overnight, poured into water andextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate and concentrated. To the residue was addedacetic acid (15.0 mL) and H₂O (5.0 mL). The reaction mixture was stirredat 100° C. for 5 hours and concentrated to remove the acetic acid. Theresidue was then treated with aqueous Na₂HCO₃ and extracted with ethylacetate. The organic layer was washed, dried, concentrated and purifiedto give compound P-0017 (1.0 g, yield=18.5%) as a light yellow solid. MS(ESI) [M+H]⁺=397.

Step-2—Synthesis of(1H-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-methanol(14)

Into a round bottom flask was added(1H-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-methanoneP-0017 (210.0 mg, 0.53 mmol) and sodium tetrahydroborate (80.0 mg, 2.11mmol), dissolved in N,N-dimethylformamide (5.0 mL) and ethanol (20.0mL). The reaction was stirred at room temperature overnight, poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, concentrated and purified withbiotage (dichloromethane/methanol 1:20) to give compound 14 (63 mg,yield=30%) as a white solid. MS (ESI) [M+H⁺]⁺=399.

Step-3—Synthesis of[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine(P-0003)

Into a round bottom flask was added(1H-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-methanol14 (200.0 mg, 0.50 mmol), trifluoroacetic acid (5.0 mL, 0.065 mol) andtriethylsilane (3.0 mL, 0.019 mol). The reaction was stirred at roomtemperature for 30 min, poured into aqueous sodium bicarbonate, andextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate, concentrated and purified to give purecompound P-0003 (120.0 mg, yield=62.8%) as a white solid. MS (ESI)[M+H⁺]⁺=383.

Example 9 Synthesis of compounds of Formula I where n is 1, P, Q and Tare CH X₁, X₂ and Y₂ are CH, Y₁ is CR⁴, L¹ is —CH₂—, L² is —NHCH₂—, andR¹ is 4 substituted phenyl (Formula Ic)

Compounds of Formula Ic, where R⁴ is as defined for Formula I (paragraph[0011]) and Z is a substituent as defined for optionally substitutedaryl, can be synthesized in five Steps from 2-amino-5-bromopyridines asshown in the following general Scheme 11.

Step-1—Preparation of Compounds of Formula V

To a solution of an appropriately substituted benzaldehyde (e.g.p-trifluoromethyl benzaldehyde) in a non-reactive solvent (e.g.tetrahydrofuran) is added an appropriate 2-amino-5-bromo-pyridine 15,followed by appropriate reagents to effect the reduction (e.g.dibutyltin dichloride and phenylsilane). Typically the reaction isheated (e.g. 50° C.) overnight. The solvent is removed at reducedpressure after heating to 50° C. overnight. Isolation by conventionalmeans (e.g. extraction) affords compounds of Formula V.

Step-2—Preparation of Compounds of Formula VI

Compound of Formula V is dissolved in a non-reactive solvent (e.g.tetrahydrofuran) and typically cooled at −78° C. under an inertatmosphere. To this mixture is added an organo lithium reagent (e.g.methyl lithium). The reaction mixture is typically stirred at −78° C.for several hours. To this mixture is added an organo lithium reagent(e.g. tert-butyl lithium), and the mixture is stirred for several hours.The reaction mixture is maintained at −78° C., and an appropriateformylating reagent (e.g. 1-piperidine carboxaldehyde) is added.Typically, the reaction is allowed to stir at −78° C. for an additionalseveral hours and slowly warmed to room temperature. Isolation byconventional means (e.g. extraction) affords compounds of Formula VI.

Step-3—Preparation of Compounds of Formula VII

Compound of Formula VI is dissolved in a non-reactive solvent (e.g.tetrahydrofuran) and stirred under an inert atmosphere. To this solutionis added a base (e.g. triethylamine) and typically a catalyst (e.g.4-dimethylaminopyridine). Typically, the mixture is stirred for a fewminutes and then a reagent appropriate for the introduction of aprotecting group (e.g. di-tert-butyldicarbonate) is added. Typically,the reaction is stirred overnight. Isolation by conventional means (e.g.extraction) affords compounds of Formula VII.

Step-4—Preparation of Compounds of Formula VIII and IX

4-Substituted 1H-pyrrolo[2,3-b]pyridine XXX is added to a stirringsolution of base (e.g. potassium hydroxide) in an appropriate polarprotic solvent (e.g. methanol). Compound of Formula VII is added, andthe mixture is typically stirred at room temperature for several days.The solvent is evaporated, and 1 M HCl is added to the residue.Isolation by conventional means (e.g. extraction, silica gelchromatography) affords compounds of Formula VIII and IX.

Step-5—Preparation of Compounds of Formula Ic

Typically, compounds of Formula VIII and IX is combined and dissolved inan appropriate polar aprotic solvent (e.g. acetonitrile). Reagentsappropriate to effect the reduction (e.g. triethylsilane andtrifluoroacetic acid) are added. Typically, the reactions are stirred atroom temperature for several days. Isolation by conventional means (e.g.extraction, silica gel chromatography) affords compounds of Formula Ic.

Example 10 Synthesis of[5-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine(P-0011)

[5-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amineP-0011 was synthesized as shown in Scheme 12:

Step 1: Preparation of(5-Bromo-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine (17)

Into a round bottom flask fitted with stirrer and reflux condenser wasadded 2-amino-5-bromopyridine (15, 1.73 mol, 300 g) andp-trifluoromethylbenzaldehyde (16, 1.723 mol, 300 g) to a solution oftrifluoroacetic acid (400 mL), triethylsilane (825 mL) and acetonitrile(7500 mL). The reaction was heated to reflux overnight (24 hours).Solvents were removed and the residue was poured into aqueous K₂CO₃ andextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate, and concentrated. The crude compound wascrystallized with diethyl ether/hexane to afford compound 17, 420 g(73.6%) as off white solid. MS (ESI) [M+H⁺]⁺=331.1 and 333.1 (1:1ratio).

Step 2: Preparation of6-(4-Trifluoromethyl-benzylamino)-pyridine-3-carbaldehyde (18)

Into a 5 L round bottom flask was added compound 17 (0.6 mol, 198.6 g,)and tetrahydrofuran (2.5 L) under an atmosphere of argon at −78° C. Intothe reaction mixture was added 1.7 M tert-butyllithium in pentane (800mL) over 60 mins. Two hours after the addition of tert-butyllithium,N,N-dimethylformamide (100 mL) was added. The reaction mixture wasstirred at −78° C. for 2 hours, then allowed to stand at roomtemperature for another 1 hour. The reaction mixture was poured intosaturated ammonium chloride solution and extracted with ethyl acetate.The organic layer was washed with brine, dried over sodium sulfate,concentrated and triturated with hexane/isopropyl ether (1:1) to givealdehyde compound 18.

Step 3: Preparation of(5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acidtert-butyl ester (19)

Into a 2 L round bottom flask was added di-tert-butyldicarbonate (90 g),aldehyde 18 (75 g), diisopropyl ethyl amine (60 g),4-dimethylaminopyridine (2.0 g,) and dichloromethane (1000.0 mL). Thereaction was stirred at room temperature overnight (18 hours) and thesolvent was evaporated to give compound 19 (94 g).

Steps 4 and 5: Preparation of[5-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine(P-0011)

Step 4: Into a solution of methanol (20 mL, 0.5 mol) was added sodiumhydroxide (0.62 g, 0.016 mol), followed by 4-methoxy-7-azaindole (20,600 mg, 4 mmol, prepared as described in Example 12). Once the mixturewas homogeneous, compound 19 (1.7 g, 4.46 mmol) was added and themixture was stirred at room temperature for 48 hours. The solvent wasevaporated and dilute HCl was added to the residue. The residue wasextracted with ethyl acetate and washed with 10% sodium bicarbonate,followed by brine. The organic layer was dried over MgSO₄, filtered andevaporated to give a mixture of crude compounds 21 and 22, which wasused in the next step.

Step 5: The mixture of 21 and 22 from Step 4 (2.36 g, 4.46 mmol) wasdissolved in dichloromethane (60 mL, 0.9 mol) to which triethylsilane(3.6 mL, 0.022 mol) and trifluoroacetic Acid (2.1 mL, 0.027 mol) wereadded. The resulting mixture was stirred for 48 hours at roomtemperature. The solvent was evaporated and the mixture was extractedwith dichloromethane:methanol (3:1). The organic layer was washed withsaturated bicarbonate followed by brine. The organic layer was driedover MgSO₄, filtered and evaporated to give crude compound as a residue.The residue was purified by flash silica gel chromatography to give 1.15g of solid P-0011 for a 60% yield.

MS (ESI) [M+H⁺]⁺=413.24.

[5-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-benzyl)-amineP-0010

was prepared following the protocol of Scheme 12, substituting4-trifluoro-benzylamine with 4-chloro-benzylamine in Step 1. MS (ESI)[M+H⁺]+=379.2 and 381.2 (3:1 ratio).

[5-(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-benzyl)-amineP-0009

was prepared following the protocol of Scheme 12, substituting4-trifluoro-benzylamine with 4-chloro-benzylamine in Step 1 and4-methoxy-7-azaindole with 4-chloro-7-azaindole (24, prepared asdescribed in Example 11) in Step 4. MS (ESI) [M+H⁺]+=381.1 and 383.0.

Example 11 Synthesis of 4-chloro-7-azaindole (24)

4-chloro-7-azaindole 24 was synthesized in two Steps from 7-azaindoleaccording to the protocol of Scheme 13.

Step-1—Synthesis of 1H-Pyrrolo[2,3-b]pyridine 7-oxide (23)

1H-Pyrrolo[2,3-b]pyridine 7-oxide 23 was synthesized by reactingcommercially available 7-azaindole 1 with an oxidizing agent (e.g.m-CPBA) in a non-reactive solvent (e.g. dimethoxyethane) as described bySchneller, S. W.; Luo, Jiann-Kuan. J. Org. Chem. 1980, 45:4045-4048. Thecompound was isolated by filtration of the resulting solid that formsupon standing at 5° C. for typically 1-3 h.

Step-2—Synthesis of 4-chloro-7-azaindole (24)

4-chloro-7-azaindole 24 was synthesized by reacting1H-Pyrrolo[2,3-b]pyridine 7-oxide 23 with a chlorinating agent (e.g.POCl₃) neat as described by Schneller, S. W.; Luo, Jiann-Kuan. J. Org.Chem. 1980, 45:4045-4048. The resulting solution after heating for 3-5 hat elevated temperatures (100-150° C.) was neutralized with a base (e.g.NH₄OH) until a solid precipitated. The solid was isolated by filtration.

Example 12 Synthesis of 4-methoxy-7-azaindole (20)

4-methoxy-7-azaindole 20 was synthesized in one Step from4-chloro-7-azaindole according to the protocol of Scheme 14.

4-methoxy-7-azaindole 20 was prepared by reacting 4-chloro-7-azaindole24 (prepared as described in Example 9) with sodium hydroxide inmethanol as described by Girgis, N. et.al., J. Heterocyclic. Chem. 1989,26:317-325.

Example 13 Synthesis of compounds of Formula I where n is 1, P is CR³⁰,Q, T, X₁, X₂, Y₁ and Y₂ are CH, L¹ is —CH₂—, L² is —NHCH₂—, and R¹ issubstituted phenyl (Formula Id)

Compounds of Formula Id, where R³⁰ is a substituent as defined foroptionally substituted heteroarylene (further defined in Scheme 13below) and R³¹ is a substituent as defined for optionally substitutedaryl, can be synthesized in six Steps from appropriately substituted2-halopyridines as shown in the following general Scheme 15.

Step 1—Preparation of Compounds of Formula XI

To an appropriately substituted 2-halopyridine X (e.g.2-chloro-6-methoxypyridine), where Y is a halogen, preferably chlorineor bromine, and R³⁰ is a group appropriate to direct the followinglithiation to the 5-position (e.g. R³⁰=methoxy), in a non-reactivesolvent (e.g. tetrahydrofuran) typically cooled in a −78° C. acetone/dryice bath is added a solution of organolithium reagent (e.g.tert-butyllithium). The reaction is allowed to stir for a period,typically 1 hour. An appropriate formylating agent (e.g.dimethylformamide) is added and the reaction is allowed to stir cooledfor a period and then warmed to room temperature for a period, typically30 minutes. The reaction can be placed back in the dry-ice bath andquenched with 6 N HCl (1.5 mL) followed by water and allowed to warm toroom temperature. Isolation by conventional means (e.g. extraction)provides compounds of Formula XI.

Step 2—Preparation of Compounds of Formula XII

To 1H-pyrrolo[2,3-b]pyridine 1 and a compound of Formula XI is added anappropriate polar solvent (e.g. methanol) followed by an appropriatebase (e.g. potassium hydroxide). The reaction is typically allowed tostir at room temperature overnight. Isolation by convention means (e.g.extraction, washing and filtering) affords compounds of Formula XII.

Step 3—Preparation of Compounds of Formula XIII

To a compound of Formula XII in an appropriate polar solvent (e.g.acetonitrile) is added a reducing agent (e.g. trifluoroacetic acid andtriethylsilane). Typically, the reaction is allowed to stir at roomtemperature overnight. Isolation by conventional means (e.g. extractionand silica gel chromatography) affords compounds of Formula XIII.

Step 4—Preparation of Compounds of Formula XIV

To a solution of compound of Formula XIII in an appropriate polarsolvent (e.g. dimethylformamide) is added a base (e.g. sodium hydride).Typically, the reaction is stirred at room temperature for 30 minutes,and then an appropriate reagent to introduce a protecting group (“P”) isadded (e.g. triisopropylsilyl chloride). The reaction typically isstirred at room temperature for several hours. Isolation by conventionalmeans (e.g. extraction and silica gel chromatography) affords compoundsof Formula XIV.

Step 5—Preparation of Compounds of Formula XVI

To a compound of Formula XIV, an appropriately substituted benzylamineXV (e.g. 4-(trifluoromethyl)benzylamine), a base (e.g. sodiumtert-butoxide), a catalyst (e.g.tris(dibenzylideneacetone)dipalladium(0)), and ligand (e.g.2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl) are added a non-reactivesolvent (e.g. toluene) under an inert atmosphere. Typically, thereaction is heated (e.g. 80° C.) for several hours. Isolation byconventional means (e.g. extraction and silica gel chromatography)affords compounds of Formula XVI.

Step 6—Preparation of Compounds of Formula Id

To compound of Formula XVI is added an appropriate polar solvent (e.g.tetrahydrofuran) followed by an appropriate reagent to remove theprotecting group (e.g. tetra-n-butylammonium fluoride). Typically, thereaction is allowed to stir at room temperature for several hours.Isolation by conventional means (e.g. extraction and silica gelchromatography) affords compounds of Formula Id.

Example 14 Synthesis of compounds of Formula I where n is 1, P is CR³²,Q, T, X₁, X₂, Y₁ and Y₂ are CH, L¹ is —CH₂—, L² is —NHCH₂—, and R¹ issubstituted phenyl (Formula Ie)

Compounds of Formula Id, where R³² is a substituent as defined foroptionally substituted heteroarylene and R³³ is a substituent as definedfor optionally substituted aryl, can be synthesized in five Steps fromappropriately substituted 2-amino-5-bromopyridines as shown in thefollowing general Scheme 16.

Step-1—Preparation of Compounds of Formula XIX

To a solution of an appropriately substituted benzaldehyde XVIII (e.g.p-trifluoromethyl benzaldehyde) in a non-reactive solvent (e.g.tetrahydrofuran) can be added an appropriate 2-amino-5-bromo-pyridineXVII (e.g. 2-amino-5-bromo-6-methylpyridine), followed by appropriatereagents to effect the reduction (e.g. dibutyltin dichloride andphenylsilane). Typically the reaction is heated (e.g. 50° C.) overnight.Isolation by conventional means (e.g. extraction) affords compounds ofFormula XIX.

Step-2—Preparation of Compounds of Formula XX

Compound of Formula XIX is dissolved in a non-reactive solvent (e.g.tetrahydrofuran) and typically cooled at −78° C. under an inertatmosphere. To this mixture is added an organolithium reagent (e.g.methyllithium). The reaction mixture is typically stirred at −78° C. forseveral hours. To this mixture is added an organolithium reagent (e.g.tert-butyllithium) and the mixture is stirred for several hours. Thereaction mixture is maintained at −78° C., and an appropriateformylating reagent (e.g. 1-piperidine carboxaldehyde) is added.Typically, the reaction is allowed to stir at −78° C. for an additionalseveral hours and slowly warmed to room temperature. Isolation byconventional means (e.g. extraction) affords compounds of Formula XX.

Step-3—Preparation of Compounds of Formula XXI

Compound of Formula XX is dissolved in a non-reactive solvent (e.g.tetrahydrofuran) and stirred under an inert atmosphere. To this solutionis added a base (e.g. triethylamine) and typically a catalyst (e.g.4-dimethylaminopyridine). Typically, the mixture is stirred for a fewminutes, and then a reagent appropriate for the introduction of aprotecting group (e.g. di-tert-butyldicarbonate) is added. Typically,the reaction is stirred overnight. Isolation by conventional means (e.g.extraction) affords compounds of Formula XXI.

Step-4—Preparation of Compounds of Formula XXII and XXIII

1H-Pyrrolo[2,3-b]pyridine 1 is added to a stirred solution of base (e.g.potassium hydroxide) in an appropriate polar solvent (e.g. methanol).Compound of Formula XXI is added, and the mixture is typically stirredat room temperature for several days. The solvent is evaporated and 1 MHCl is added to the residue. Isolation by conventional means (e.g.extraction, silica gel chromatography) affords compounds of Formula XXIIand XXIII.

Step-5—Preparation of Compounds of Formula Ie

Typically, compounds of Formula XII and XIII are combined and dissolvedin an appropriate polar aprotic solvent (e.g. acetonitrile). Reagentsappropriate to effect the reduction (e.g. triethylsilane andtrifluoroacetic acid) are added. Typically, the reaction is stirred atroom temperature for several days. Isolation by conventional means (e.g.extraction, silica gel chromatography) affords compounds of Formula Ie.

Example 15 Synthesis of[6-Methoxy-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine(P-0012)

[6-Methoxy-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amineP-0012 was synthesized in five steps from commercially available2-chloro-6-methoxypyridine and 7-azaindole as shown in Scheme 17.

Step 1—Preparation of 6-chloro-2-methoxypyridine-3-carbaldehyde (26)

To 2-Chloro-6-methoxypyridine (25, 0.511 g, 3.56 mmol) intetrahydrofuran (10 mL) cooled in a −78° C. acetone/dry ice bath wasadded tert-butyllithium (1.7 M in pentane, 5.0 mL, 7.66 mmol). Thereaction was allowed to stir for 1 hour. Dimethylformamide (0.673 mL,17.4 mmol) was added and the reaction was allowed to continue for anadditional 30 minutes at −78° C., then stirred for 30 minutes outside ofthe dry-ice bath. The reaction was placed back in the dry-ice bath andquenched with 6 N HCl (1.5 mL) followed by water and allowed to warm toroom temperature. The reaction was extracted with diethyl ether andaqueous (1M) sodium bicarbonate. The organic layer was separated, driedwith anhydrous magnesium sulfate, filtered and volatiles removed byrotary evaporation, and the resulting yellow solid was dried undervacuum to provide 561 mg of compound 26 (3.27 mmol, 92% yield). MS (ESI)[M+H⁺]⁺=172.0.

Step 2—Preparation of (6-chloro-2-methoxypyridin-3-yl)(1H-pyrrolo[2,3-b]pyridin-3-yl)methanol (27)

To 1H-Pyrrolo[2,3-b]pyridine (1, 0.455 g, 3.85 mmol) and6-chloro-2-methoxypyridine-3-carbaldehyde (26, 0.661 g, 3.85 mmol) wasadded methanol (10 mL) followed by potassium hydroxide (0.310 g, 5.52mmol). The reaction was allowed to stir at room temperature overnight.The reaction was extracted with diethyl ether/ethyl acetate and water.The organic layer was separated, dried over anhydrous magnesium sulfate,filtered and volatiles were removed by rotary evaporation to provide asolid that was treated with dichloromethane and stored in a freezerovernight. The white solid was collected by vacuum filtration and driedin vacuo to give 613 mg of compound 27 (2.12 mmol, 55%). MS (ESI)[M+H⁺]⁺=290.1.

Step 3—Preparation3-(6-chloro-2-methoxypyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (28)

To(6-chloro-2-methoxypyridin-3-yl)(1H-pyrrolo[2,3-b]pyridin-3-yl)methanol(27, 0.613 g, 2.12 mmol) in acetonitrile (10 mL) was addedtrifluoroacetic acid (0.82 mL, 10.0 mmol) followed by triethylsilane(1.69 mL, 10.6 mmol). The reaction was allowed to stir at roomtemperature for 2 days, then 60° C. for 4 hours. The reaction wasextracted with diethyl ether and aqueous sodium bicarbonate. The organiclayer was dried over anhydrous magnesium sulfate and filtered. Thedesired material was isolated from the filtrate by silica gel columnchromatography eluting with 1% methanol in dichloromethane to give 516mg of a white solid compound 28 (1.88 mmol, 89%). MS (ESI)[M+H⁺]⁺=274.1.

Step 4—Preparation3-(6-chloro-2-methoxypyridin-3-ylmethyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine(29)

To a clear solution of3-(6-chloro-2-methoxypyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (28,0.516 g, 1.88 mmol) in dimethylformamide (10 mL) was added sodiumhydride (60% dispersion, 0.113 g, 2.82 mmol). After stirring at roomtemperature for 30 minutes, triisopropylsilyl chloride (600 L, 2.83mmol) was added. The reaction was stirred at room temperature for 2hours, then poured into aqueous (1M) sodium bicarbonate and extractedwith ethyl acetate. The organic layer was separated, dried (magnesiumsulfate), filtered and volatiles were removed by rotary evaporation togive a crude solid. The compound was purified by silica gel columnchromatography eluting with 2% ethyl acetate in hexanes. This provided732 mg of the desired compound as a white, crystalline solid (29, 1.70mmol, 90%). MS (ESI) [M+H⁺]⁺=430.2.

Step 5—Preparation of[6-Methoxy-5-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine(31)

3-(6-chloro-2-methoxypyridin-3-ylmethyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine(29, 0.104 g, 0.242 mmol), 4-(Trifluoromethyl)benzylamine (30, 0.047 g,0.266 mmol), sodium tert-butoxide (0.0325 g, 0.338 mmol),Tris(dibenzylideneacetone)-dipalladium (0) (0.00062 g, 0.0006 mmol), and2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.0011 g, 0.0018 mmol) wereadded to toluene (2 mL) under nitrogen. The reaction vial was placed inan oil bath at 80° C. for 3 hours. The reaction was poured into waterand extracted with ethyl acetate. The organic layer was dried (magnesiumsulfate), filtered, and volatiles were removed by rotary evaporation.The residue was purified by silica gel column chromatography elutingwith 2% ethyl acetate in hexanes. This provided 34 mg of the desiredcompound 31 (0.060 mmol, 25%). MS (ESI) [M+H⁺]⁺=569.3.

Step 6—Preparation of[6-Methoxy-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine(P-0012)

To[6-Methoxy-5-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine(31, 0.0340 g, 0.0598 mmol) was added tetrahydrofuran (5 mL) followed bytetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 66 μL,0.0658 mmol). The reaction was allowed to stir at room temperature for 2hours, then poured into 1:1 water:saturated sodium bicarbonate andextracted with ethyl acetate. The organic layer was separated, driedover magnesium sulfate, filtered and the volatiles were removed byrotary evaporation. The resulting residue was purified by silica gelcolumn chromatography, eluting with dichloromethane followed by 1%methanol in dichloromethane and finally 3% methanol in dichloromethane.This provided 20 mg of the desired compound as a white solid (P-0012,0.048 mmol, 81%). MS (ESI) [M+H⁺]⁺=413.2.

Example 16 Synthesis of[6-Methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine(P-0013)

[6-Methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine(P-0013) was synthesized in five steps from commercially available2-amino-5-bromo-6-methylpyridine and 7-azaindole as shown in Scheme 18.

Step-1—Preparation of(5-Bromo-6-methyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine (34)

To a solution of p-trifluoromethylbenzaldehyde (16, 1.00 g, 5.74 mmol)in tetrahydrofuran (9 mL) was added 2-amino-5-bromo-6-methylpyridine(33, 1.08 g, 5.77 mmol), followed by dibutyltin dichloride (40 mg, 0.13mmol). The mixture was stirred for 5 minutes at 25° C. and phenylsilane(0.69 g, 6.4 mmol) was added. The reaction was heated at 50° C.overnight, then the solvent was removed at reduced pressure. Ethylacetate was added to the resulting solid which was washed with saturatedsodium carbonate, dried over magnesium sulfate and filtered.Concentration under reduced pressure afforded a light yellow solid (34,1.7 g, 4.93 mmol). MS (ESI) [M+H⁺]⁺=345.1.

Step-2—Preparation of2-Methyl-6-(4-trifluoromethyl-benzylamino)-pyridine-3-carbaldehyde (35)

(5-Bromo-6-methyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine (34,1.7 g, 4.93 mmol) was dissolved in tetrahydrofuran (40 mL) and cooled at−78° C. under a nitrogen atmosphere. To this mixture was addedmethyllithium (1.6 M in diethyl ether, 5.91 mmol) dropwise over 20minutes. After the addition of methyllithium was completed, the reactionmixture was stirred at −78° C. for 2 hours. To this mixture was addedtert-butyllithium (1.7 M in pentane, 10.85 mmol) and the mixture wasstirred for 4 hours. The reaction mixture was maintained at −78° C., and1-piperidinecarboxaldehyde (0.60 mL, 5.42 mmol) was added dropwise. Thereaction was allowed to stir at −78° C. for an additional 2 hours andwarming to ° C. was achieved from the slow evaporation of the dryice/acetone cooling bath. The reaction was quenched with ice coldsaturated sodium chloride and the resulting mixture was extracted withethyl acetate. The organic layer was dried over magnesium sulfate andfiltered. Concentration under reduced pressure afforded an orange oil(35, 1.4 g, 4.93 mmol).

MS (ESI) [M+H⁺]⁺=295.1.

Step-3—Preparation of(5-Formyl-6-methyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamicacid tert-butyl ester (36)

2-Methyl-6-(4-trifluoromethyl-benzylamino)-pyridine-3-carbaldehyde (35,1.4 g, 4.9 mmol) was dissolved in tetrahydrofuran (22 mL) and wasstirred under an atmosphere of nitrogen. To this solution was added4-dimethylaminopyridine (150 mg, 1.23 mmol) and triethylamine (0.66 mL,4.9 mmol). The mixture was stirred for 5 minutes before soliddi-tert-butyldicarbonate (1.0 g, 4.9 mmol) was added directly to thereaction mixture. The mixture was stirred overnight at 25° C. and wasdiluted with ethyl acetate and washed with sodium bicarbonate, followedby washing with saturated sodium chloride. The resulting organic layerwas dried over magnesium sulfate, filtered and evaporated to give abeige solid (36, 1.8 g, 4.6 mmol). MS (ESI) [M+H⁺]⁺=395.2.

Step-4—Preparation of{5-[Hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-6-methyl-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-carbamicacid tert-butyl ester (37) and{5-[Methoxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-6-methyl-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-carbamicacid tert-butyl ester (38)

1H-Pyrrolo[2,3-b]pyridine (1, 540 mg, 4.57 mmol) was added to a stirringsolution of potassium hydroxide (868 mg, 10.08 mmol) in methanol (33mL). Once the mixture was homogeneous,(5-formyl-6-methyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamicacid tert-butyl ester (36, 1.8 g, 4.6 mmol) was added and the mixturewas stirred at 25° C. for 72 hours. The solvent was evaporated and 1 MHCl was added to the residue. The organic material was extracted withethyl acetate and washed with 10% sodium bicarbonate, followed bywashing with saturated sodium chloride. The organic layer was dried overmagnesium sulfate. Concentration under reduced pressure afforded thecrude material, which was purified by silica gel column chromatography(0-5% methanol in dichloromethane) to yield the desired compounds as alight yellow solid (37 and 38 as a mixture, 294 mg; 13% yield).

MS (ESI) [M+H⁺]⁺=511.2 for 37 and MS (ESI) [M+H⁺]⁺=525.2 for 38.

Step-5 Preparation of[6-Methyl-5-(1H-pyrrolo[2,3-b]bipyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine(P-0013)

The combined materials of{5-[Hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-6-methyl-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-carbamicacid tert-butyl ester (37) and{5-[Methoxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-6-methyl-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-carbamicacid tert-butyl ester (38) (194 mg, 0.378 mmol) were dissolved inacetonitrile (3 mL) and triethylsilane (0.30 mL, 1.9 mmol) andtrifluoroacetic acid (0.17 mL, 2.3 mmol) were added. After stirring at25° C. for overnight, TLC analysis indicated that the reaction was about50% complete. To the reaction mixture was added triethylsilane (0.30 mL,1.9 mmol), and trifluoroacetic acid (0.17 mL, 2.3 mmol). The mixture wasallowed to stir for another 48 hours at 25° C. and the solvent, excesstriethylsilane and trifluoroacetic acid were removed by evaporation.Ethyl acetate was added and washed with saturated sodium bicarbonate.The organic layer was dried over magnesium sulfate, filtered andconcentrated at reduced pressure to afford a brown oil. Purification of80 mg of the crude material was carried out using preparatorychromatography (50% ethyl acetate in hexanes) to afford the compound asan off-white solid (P-0013, 10 mg, 0.025 mmol).

MS (ESI) [M+H⁺]⁺=397.2.

(4-Chloro-benzyl)-[6-methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0014

was prepared following the protocol of Scheme 18, substituting4-trifluoromethyl benzaldehyde with 4-chlorobenzaldehyde (40) in Step 1.MS (ESI) [M+H⁺]+=363.1.

Example 17 Synthesis of[5-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-benzyl)-amine(P-0038)

[5-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-benzyl)-amineP-0038 was synthesized in 5 steps from commercially available2-Amino-5-bromopyridine 15 as shown in Scheme 19.

Step 1—Synthesis of (5-Bromo-pyridin-2-yl)-(4-chloro-benzyl)-amine (41)

To 2-Amino-5-bromopyridine (15, 6.10 g, 0.0352 mol) in toluene (90.0 mL)were added 4-chlorobenzaldehyde (40, 5.00 g, 0.0356 mol),trifluoroacetic acid (8.0 mL, 0.10 mol) and triethylsilane (16.5 mL,0.103 mol). The reaction was heated to reflux for 48 hours. The reactionwas concentrated, poured into aqueous potassium carbonate and extractedwith ethyl acetate. The organic layer was washed with brine, dried oversodium sulfate and concentrated. The crude residue was crystallized withethyl acetate to give compound (41, 6.8 g, 65.4%).

Step 2—Synthesis of 6-(4-Chloro-benzylamino)-pyridine-3-carbaldehyde(42)

To (5-Bromo-pyridin-2-yl)-(4-chloro-benzyl)-amine (41, 10.00 g, 0.03360mol) in tetrahydrofuran (400.0 mL) under an atmosphere of nitrogen at−78° C. was added n-butyllithium (17.5 mL, 2.00 M in cyclohexane). After90 minutes, tert-butyllithium (42.00 mL, 1.70 M in hexane) was added tothe reaction. After 80 minutes, N,N-dimethylformamide (6.9 mL, 0.089mol) was added to the reaction. The reaction mixture was stirred at −78°C. for 2 hours, then allowed to warm to room temperature for 1 hour. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with brine, dried over sodium sulfate andconcentrated to give the crude compound, which was crystallized fromtert-butoxyl methyl ether to provide compound (42, 7.66 g, 92.2%).

Step 3—Synthesis of (4-Chloro-benzyl)-(5-formyl-pyridin-2-yl)-carbamicacid tert-butyl ester (43)

To 6-(4-Chloro-benzylamino)-pyridine-3-carbaldehyde (42, 2.00 g, 8.11mmol) in dichloromethane (20.0 mL) were added triethylamine (1.70 mL,12.2 mmol), di-tert-butyldicarbonate (2.00 g, 9.16 mmol) and4-dimethylaminopyridine (52.3 mg, 0.43 mmol). The reaction was stirredat room temperature for 48 hours. The reaction was concentrated andpurified by silica gel column chromatography eluting with 20% ethylacetate in hexane to give compound (43, 2.50 g, 89.3%).

Step 4—Synthesis of{5-[(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl}-(4-chloro-benzyl)-carbamicacid tert-butyl ester (45)

To 5-bromo-7-azaindole (44, 198.0 mg, 1.01 mmol) in methanol (30.0 mL,0.741 mol) were added (4-Chloro-benzyl)-(5-formyl-pyridin-2-yl)-carbamicacid tert-butyl ester (43, 355.0 mg, 1.02 mmol) and potassium hydroxide(80.0 mg, 1.42 mmol). The reaction was stirred at room temperature 48hours. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, concentrated and purified by silica gel columnchromatography eluting with 8% methanol in dichloromethane to givecompound (45, 200.0 mg, 36.8%).

Step 5—Synthesis of[5-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-benzyl)-amine(P-0038)

To{5-[(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl}-(4-chloro-benzyl)-carbamicacid tert-butyl ester (45, 180.0 mg, 0.33 mmol) in acetonitrile (30.0mL) were added trifluoroacetic acid (2.0 mL, 0.026 mol) andtriethylsilane (4.0 mL, 0.025 mol). The reaction was heated to refluxfor 4 hours. The reaction mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, concentrated and purified by silica gel columnchromatography eluting with 10% methanol in dichloromethane to givecompound (P-0038, 120 mg, 85.2%).

MS (ESI)[M+H⁺]⁺=427.2, 429.2.

Additional compounds were prepared following the protocol of Scheme 19,optionally replacing 4-chlorobenzaldehyde 40 with an appropriatealdehyde in Step 1 and optionally replacing 5-bromo-7-azaindole 44 withan appropriate azaindole in Step 4. The following compounds were madefollowing this procedure:

-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0181),-   [5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0182),-   3-[6-(4-Chloro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0257),-   3-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0269),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-fluoro-benzyl)-amine    (P-0270),-   3-[6-(2-Fluoro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0271),-   (2-Fluoro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0272),-   3-{6-[(6-Trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0273),-   3-[6-(2-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0274),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0275),-   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0276),-   3-[6-(2,6-Difluoro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0277),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,6-difluoro-benzyl)-amine    (P-0278),-   (2-Chloro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0279),-   (2-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0280),-   3-[6-(2-Chloro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0281),-   (6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0282),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine    (P-0283),-   3-{6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0284),-   (2-Methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0285),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-methoxy-pyridin-3-ylmethyl)-amine    (P-0286),-   3-{6-[(2-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0287),-   (2-Ethoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0288),-   (2,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0296),-   (2,5-Difluoro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0297),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,5-difluoro-benzyl)-amine    (P-0298),-   3-[6-(2,5-Difluoro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0299),-   3-[6-(2-Trifluoromethoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0321),-   [5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethoxy-benzyl)-amine    (P-0322),-   3-[6-(2-Ethoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0323),-   [5-(5-Fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0325),-   [5-(5-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0326),-   (2-Chloro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0327),-   (2-Chloro-benzyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0328),-   (2,5-Difluoro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0329),-   (2,5-Difluoro-benzyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0330),-   [5-(5-Fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine    (P-0331),-   (6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0332),-   (2,6-Difluoro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0333),-   (2,6-Difluoro-benzyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0334),-   (2-Methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0336),-   3-[6-(2-Methoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0337),-   (2,6-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0340), and-   (2,6-Difluoro-benzyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0341).    The following table indicates the aldehyde used in Step 1 in Column    3 and the azaindole used in Step 4 in Column 2 to provide the    compound of Column 4. Column 1 provides the compound number and    Column 5 the measured mass spectrometry result.

Compound Azaindole Aldehyde MS number in Step 4 in Step 1 Compoundstructure [M + H⁺]⁺ P-0181

418.2 P-0182

384.2 P-0257

374.2 P-0269

408.7 P-0270

367.0 P-0271

358.0 P-0272

347.0 P-0273

409.4 P-0274

408.5 P-0275

417.0 P-0276

397.6 P-0277

376.5 P-0278

385.0 P-0279

363.0 P-0280

383.3 P-0281

374.0 P-0282

360.8 P-0283

380.0 P-0284

371.5 P-0285

360.1 P-0286

380.0 P-0287

371.0 P-0288

359.6 P-0296

351.6 P-0297

365.5 P-0298

385.9 P-0299

376.4 P-0321

424.6 P-0322

399.5 P-0323

384.7 P-0325

401.5 P-0326

413.4 P-0327

367.2 P-0328

379.0 P-0329

369.7 P-0330

381.6 P-0331

364.5 P-0332

376.4 P-0333

369.6 P-0334

381.6 P-0336

345.7 P-0337

370.7 P-0340

351.5 P-0341

365.5

Additional compounds were prepared following the protocol of Scheme 19,Steps 4 and 5, replacing(4-Chloro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester43 with an appropriate protected aldehyde and 5-bromo-7-azaindole 44with an appropriate azaindole in Step 4. Aldehydes were prepared asdescribed in Example 60. The following compounds were made followingthis procedure:

-   3-{2-Chloro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0232),-   [6-Chloro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0233),-   [6-Chloro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0234),-   (3-Chloro-pyridin-4-ylmethyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0235),-   3-{6-[(3-Chloro-pyridin-4-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0256),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-difluoromethoxy-benzyl)-amine    (P-0338),-   3-[6-(2-Difluoromethoxy-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile    (P-0339),

The following table indicates the aldehyde used in Column 2 and theazaindole used in Column 3 to provide the compound of Column 4. Column 1provides the compound number and Column 5 the measured mass spectrometryresult.

Compound MS number Aldehyde Azaindole Compound [M + H⁺]⁺ P-0232

443.0 P-0233

[M − H⁺]⁻ = 446.1 P-0234

430.1 P-0235

383.9 P-0256

375.2 P-0338

415.0 P-0339

406.6

Example 18 Synthesis of1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde 47

Compound 47 was synthesized in 2 steps from 7-azaindole 1 as describedin Scheme 20.

Step 1—Preparation of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (46)

To 1H-Pyrrolo[2,3-b]pyridine (1, 16.0 g, 135 mmol) in water (110 mL),were added hexamethylenetetramine (26.0 g, 185 mmol), and acetic acid(55.0 mL, 967 mmol). The reaction was refluxed for 12 hours. Water (329mL) was added and the reaction was cooled to room temperature. Thereaction was filtrated and washed with water to give compound

(46, 15.0 g, 76%). MS (ESI)[M+H⁺]⁺=147.

Step 2—Preparation of1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (47)

To 1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (46, 4.05 g, 27.71 mmol) intetrahydrofuran (30.0 mL) were added sodium hydride (60% in mineral oil,1.5 g, 38 mmol) and triisopropylsilyl chloride (8.0 mL, 38 mmol) underan atmosphere of nitrogen. The reaction was stirred for 2 hours at roomtemperature. The reaction was poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 10% ethyl acetate inhexane to give compound (47, 3.0 g, 36%).

MS (ESI)[M+H⁺]⁺=303.

1-(tert-Butyl-dimethyl-silanyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine 66

was prepared following the protocol of Scheme 20 Step 2, substituting1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde 46 with3-iodo-1H-pyrrolo[2,3-b]pyridine and triisopropylsilyl chloride withtert-Butyl-dimethyl-silyl chloride.

1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde 55

was prepared following the protocol of Scheme 20, substitutingtriisopropylsilyl chloride with benzenesulfonyl chloride in Step 2.

Example 19 Synthesis ofN-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-4-trifluoromethyl-benzenesulfonamide(P-0071)

N-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-4-trifluoromethyl-benzenesulfonamideP-0071 was synthesized in 3 steps from 2-Amino-5-bromopyridine 15 asshown in Scheme 21.

Step 1—Synthesis ofN-(5-Bromo-pyridin-2-yl)-4-trifluoromethyl-benzenesulfonamide (49)

To 2-Amino-5-bromopyridine (15, 1.50 g, 8.67 mmol) in acetonitrile (20.0mL) were added pyridine (6.0 mL, 0.074 mol), 4-dimethylaminopyridine(0.10 g, 0.82 mmol) and 4-trifluoromethyl-benzenesulfonyl chloride (48,2.14 g, 8.75 mmol). The reaction mixture was stirred at room temperatureovernight. The reaction was concentrated, poured into water, acidifiedwith 1N HCl to pH=2, and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate andconcentrated. The residue was washed with ethyl acetate to give a whitesolid as desired compound (49, 2.80 g, 84.8%). MS (ESI) [M+H⁺]⁺=381.0,383.0.

Step 2—Synthesis ofN-5-[Hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl-4-trifluoromethyl-benzenesulfonamide(50)

To N-(5-Bromo-pyridin-2-yl)-4-trifluoromethyl-benzenesulfonamide (49,0.96 g, 2.5 mmol) in tetrahydrofuran (50.0 mL) under an atmosphere ofnitrogen at −78° C., tert-butyllithium (4.62 mL, 1.70 M in hexane) wasadded slowly. After 15 minutes,1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (47, 0.30g, 0.99 mmol, prepared as described in Example 18) in tetrahydrofuran(15.0 mL) was added to the reaction. After 30 minutes, the reaction wasallowed to come to room temperature for 10 minutes. The reaction waspoured into water, acidified with 1N HCl to pH around 2, and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated and purified bysilica gel column chromatography eluting with 20% ethyl acetate inhexane to give a white solid compound (50, 0.55 g, 90.1%). MS (ESI)[M+H⁺]⁺=605.3.

Step 3—Synthesis ofN-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-4-trifluoromethyl-benzenesulfonamide(P-0071)

ToN-5-[Hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl-4-trifluoromethyl-benzenesulfonamide(50, 0.27 g, 0.45 mmol) in acetonitrile (15.0 mL) were addedtrifluoroacetic acid (1.0 mL, 0.013 mol) and triethylsilane (2.0 mL,0.012 mol). The reaction was heated to 85° C. for 1 hour. The reactionwas concentrated, poured into water and extracted with ethyl acetate.The organic layer was purified with silica gel column chromatographyeluting with 50% ethyl acetate in hexane to give a white solid compound(P-0071, 28.5 mg, 14.7%). MS (ESI) [M+H⁺]^(+=433.2.)

4-Chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamideP-0074

was prepared following the protocol of Scheme 21, substituting4-trifluoromethyl-benzenesulfonyl chloride 48 with 4-chloro-benzoylchloride in step 1. MS (ESI) [M+H⁺]+=363.2.

Example 20 Synthesis ofN-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-4-trifluoromethyl-benzamide(P-0072)

N-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-4-trifluoromethyl-benzamideP-0072 was synthesized in one step from(3-(6-Bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine6a as shown in Scheme 22.

Step 1—Synthesis ofN-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-4-trifluoromethyl-benzamide(P-0072)

To 3-(6-Bromo-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (6a, 50.0mg, 0.000174 mol, prepared as described in Example 2) in 1,4-dioxane(4.0 mL) were added 4-trifluoromethyl-benzamide (51, 70.0 mg, 0.37mmol), Xanthphos (15.0 mg, 0.026 mmol), cesium carbonate (130.0 mg, 0.40mmol) and Tris(dibenzylideneacetone)-dipalladium(0) (25.0 mg, 0.024mmol) under an atmosphere of nitrogen. The reaction was heated to 120°C. for 10 minutes in a CEM Discover microwave instrument. The reactionwas poured into water and extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated and purified by silica gel column chromatographyeluting with 50% ethyl acetate in hexane to give a white solid (P-0072,4.7 mg, 6.8%). MS (ESI) [M+H⁺]⁺=397.2.

4-Fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamideP-0073

was prepared following the protocol of Scheme 22, substituting4-trifluoromethyl-benzamide with 4-fluoromethyl-benzamide. MS (ESI)[M+H⁺]+=347.2.

Example 21 Synthesis of(4-Chloro-phenyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylmethyl]-amine(P-0078)

(4-Chloro-phenyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylmethyl]-amineP-0078 was synthesized in 3 steps from 5-Bromo-pyridine-2-carbaldehyde52 as shown in Scheme 23.

Step 1—Synthesis of (5-Bromo-pyridin-2-ylmethyl)-(4-chloro-phenyl)-amine(54)

To 5-Bromo-pyridine-2-carbaldehyde (52, 1.00 g, 5.38 mmol) inacetonitrile (50.0 mL) were added p-chloroaniline (53, 0.686 g, 5.38mmol), triethylsilane (6.00 mL, 0.0376 mol) and trifluoroacetic acid(3.00 mL, 0.0389 mol). The reaction was heated to reflux for 3 hours.The reaction was concentrated, poured into water and then extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 20% ethyl acetate in hexane to give awhite solid (54, 0.75 g, 47.0%).

Step 2—Synthesis of(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-[(4-chloro-phenylamino)-methyl]-pyridin-3-yl-methanol(56)

To (5-Bromo-pyridin-2-ylmethyl)-(4-chloro-phenyl)-amine (54, 0.380 g,1.28 mmol) in tetrahydrofuran (15.0 mL) under an atmosphere of nitrogenat −78° C. was added n-butyllithium (0.850 mL, 1.60 M in hexane). After10 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (0.135 g, 0.627mmol) in tetrahydrofuran (5.0 mL) was added to the reaction. Thereaction was allowed to warm to room temperature for 40 minutes. Thereaction was cooled to −78° C., followed by addition of 1.70 Mtert-butyllithium in hexane (1.58 mL). After minutes,1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (55, 0.380 g,1.33 mmol, prepared as described in Example 18) in tetrahydrofuran (10.0mL) was added to the reaction. After 20 minutes, the reaction wasallowed to warm to room temperature. The reaction was poured into waterand extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 50% ethylacetate in hexane to give compound (56, 0.30 g, 46.0%). MS (ESI)[M+H⁺]⁺=505.3.

Step3-(4-Chloro-phenyl)-5-[methoxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-ylmethyl-amine(57)

To(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-[(4-chloro-phenylamino)-methyl]-pyridin-3-yl-methanol(56, 120.0 mg, 0.24 mmol) in methanol (20.0 mL) were added potassiumhydroxide (0.400 g, 7.13 mmol) and water (5.0 mL, 0.28 mol). Thereaction was heated to 50° C. for 10 hours. The reaction was poured intowater and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 20% ethylacetate in hexane to give compound (57, 30 mg, 33.0%). MS (ESI)[M+H⁺]⁺=379.4.

Step 4—Synthesis of(4-Chloro-phenyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylmethyl]-amine(P-0078)

To(4-Chloro-phenyl)-5-[methoxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-ylmethyl-amine(57, 20.8 mg, 0.055 mmol) in acetonitrile (10.0 mL) were addedtrifluoroacetic acid (0.50 mL, 6.5 mmol) and triethylsilane (1.00 mL,6.26 mmol). The reaction was heated to reflux for 3 hours, then pouredinto water and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 10% methanol in dichloromethane to give compound (P-0078, 6.1 mg,32.0%). MS (ESI) [M+H⁺]⁺=349.4.

Example 22 Synthesis of(4-Chloro-benzyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0082)

(4-Chloro-benzyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0082 was synthesized in 8 steps from 2,6-Difluoropyridine 58 as shownin Scheme 24.

Step 1—Synthesis of 2,6-Difluoro-nicotinic acid (59)

To 2,6-difluoropyridine (58, 7.10 g, 0.0617 mol) in tetrahydrofuran(150.0 mL) under an atmosphere of nitrogen at −78° C., n-butyllithium(26.0 mL, 2.50 M in hexane) was added slowly. After 30 minutes, dry ice(3.0 g) was added to the reaction. After 1 hour, the reaction wasallowed to warm to room temperature, then poured into water andextracted with ethyl acetate. The aqueous layer was acidified with 1 NHCl to pH=4-5 and extracted with ethyl acetate. The organic layer wasdried over anyhydrous sodium sulfate, filtered and concentrated to givethe crude compound as a light yellow solid (59, 5.6 g, 57.0%).

Step 2—Synthesis of 2,6-Difluoro-nicotinic acid methyl ester (60)

To 2,6-difluoro-nicotinic acid (59, 5.60 g, 0.0352 mol) in methanol(60.0 mL) was added concentrated sulfuric acid (1.0 mL, 0.019 mol). Thereaction was heated to reflux overnight, then poured into water,basified with 1M potassium carbonate to pH around 9, and extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand concentrated to give a yellow oil (60, 3.5 g, 57.0%).

Step 3—Synthesis of 6-(4-Chloro-benzylamino)-2-fluoro-nicotinic acidmethyl ester (62)

To 2,6-difluoro-nicotinic acid methyl ester (60, 2.00 g, 0.0116 mol) inN,N-dimethylformamide (20.0 mL), under an atmosphere of nitrogen at −40°C., was added p-chlorobenzylamine (61, 2.60 mL, 0.0214 mol). Thereaction was stirred at −40° C. to −20° C. for 2 hours, then poured intowater and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 25% ethylacetate in hexane to give compound (62, 2.0 g, 58.7%).

Step 4—Synthesis of[6-(4-Chloro-benzylamino)-2-fluoro-pyridin-3-yl]-methanol (63)

To 6-(4-Chloro-benzylamino)-2-fluoro-nicotinic acid methyl ester (62,2.00 g, 6.79 mmol) in tetrahydrofuran (100.0 mL) was added lithiumtetrahydroaluminate (13.6 mL, 1.00 M in Tetrahydrofuran) under anatmosphere of nitrogen. The reaction was stirred at room temperatureovernight. To the reaction was added an excessive amount of NaSO₄.10H₂O,and then stirred for 1 hour. Filtration, concentration and purificationwith silica gel column chromatography eluting with 30% ethyl acetate inhexane provided compound 63 (1.0 g, 55.0%).

Step 5—Synthesis of6-(4-Chloro-benzylamino)-2-fluoro-pyridine-3-carbaldehyde (64)

To [6-(4-Chloro-benzylamino)-2-fluoro-pyridin-3-yl]-methanol (63, 1.0 g,3.7 mmol) in tetrahydrofuran (50.0 mL) was added Dess-Martin periodinane(1.75 g, 4.12 mmol). The reaction was stirred at room temperature for 10minutes, then poured into water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 20% ethyl acetate in hexane to give a whitesolid (64, 0.67 g, 68.0%).

Step 6—Synthesis of(4-Chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester (65)

To 6-(4-Chloro-benzylamino)-2-fluoro-pyridine-3-carbaldehyde (64, 670.0mg, 2.53 mmol) in dichloromethane (16.2 mL) were addeddi-tert-butyldicarbonate (1.23 g, 5.65 mmol) and 4-dimethylaminopyridine(16.2 mg, 0.133 mmol). The reaction was stirred at room temperatureovernight. The reaction was concentrated and purified by silica gelcolumn chromatography eluting with 30% ethyl acetate in hexane to give awhite solid (65, 0.63 g, 68.0%).

Step 7—Synthesis of(5-[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-hydroxy-methyl-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-carbamicacid tert-butyl ester (67)

To 1-(tert-butyl-dimethyl-silanyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine (66,0.53 g, 0.0015 mol) and tetrahydrofuran (15.0 mL), under an atmosphereof nitrogen at −20° C., was added isopropylmagnesium chloride (0.78 mL,2.0 M in tetrahydrofuran). The reaction was allowed to warm to 0° C.(around 80 minutes), then cooled to −20° C., followed by addition of(4-Chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester (65, 0.200 g, 0.55 mmol) in tetrahydrofuran (6.0 mL).The reaction was allowed to warm to room temperature in 1 hour, thenpoured into water and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% ethyl acetate in hexane to give a yellow solid (67, 0.20 g,61.1%). MS (ESI) [M+H⁺]⁺=597.4.

Step 8—Synthesis of(4-Chloro-benzyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0082)

To(5-[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-hydroxy-methyl-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-carbamicacid tert-butyl ester (67, 0.10 g, 0.17 mmol) in acetonitrile (10.0 mL)were added triethylsilane (1.00 mL, 6.26 mmol) and trifluoroacetic acid(0.50 mL, 6.5 mmol). The reaction was heated to reflux for 2 hours, thenpoured into aqueous potassium carbonate, and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 30% ethyl acetate in hexane to give awhite solid (P-0082, 43.2 mg, 70.0%). MS (ESI) [M+H⁺]⁺=367.4.

Example 23 Synthesis of(4-Chloro-benzyl)-[6-methoxy-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0081)

(4-Chloro-benzyl)-[6-methoxy-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0081 was synthesized in 2 steps from(4-Chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester 65 as shown in Scheme 25.

Step 1—Synthesis of(4-Chloro-benzyl)-5-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-6-methoxy-pyridin-2-yl-carbamicacid tert-butyl ester (68)

To 1H-Pyrrolo[2,3-b]pyridine (1, 90.0 mg, 0.76 mmol) in methanol (30.0mL) were added(4-chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester (65, 300.0 mg, 0.82 mmol) and potassium hydroxide(720.0 mg, 12.83 mmol) under an atmosphere of nitrogen. The reaction wasstirred at room temperature for 2 hours, then poured into water andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 20% ethyl acetate inhexane to give the compound (68, 60 mg, 15.9%). MS (ESI) [M+H⁺]⁺=495.3.

Step 2—Synthesis of(4-Chloro-benzyl)-[6-methoxy-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0081)

To(4-Chloro-benzyl)-5-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-6-methoxy-pyridin-2-yl-carbamicacid tert-butyl ester (68, 40.0 mg, 0.081 mmol) in acetonitrile (10.0mL) were added trifluoroacetic acid (0.30 mL, 0.0039 mol) andtriethylsilane (0.60 mL, 0.0038 mol). The reaction was heated to refluxfor 3 hours. The reaction was concentrated to remove the solvents, thenpurified with silica gel column chromatography eluting with 40% ethylacetate in hexane to give compound (P-0081, 10 mg, 32.7%). MS (ESI)[M+H⁺]⁺=379.4.

Example 24 Synthesis of5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridine-2-carboxylic acid(4-chloro-phenyl)-amide (P-0076)

5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridine-2-carboxylic acid(4-chloro-phenyl)-amide P-0076 was synthesized in 3 Steps from5-Bromo-pyridine-2-carbonyl chloride 69 as shown in Scheme 26.

Step 1—Synthesis of 5-Bromo-pyridine-2-carboxylic acid(4-chloro-phenyl)-amide (70)

To 5-Bromo-pyridine-2-carbonyl chloride (69, 0.76 g, 3.4 mmol) inacetonitrile (29.0 mL) were added p-chloroaniline (53, 0.702 g, 5.50mmol), 4-dimethylamino-pyridine (0.12 g, 0.96 mmol) and pyridine (2.9mL, 0.036 mol). The reaction was stirred at 68° C. overnight, thenpoured into water, acidified with 1 N HCl to pH around 1 and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated and purified bysilica gel column chromatography eluting with dichloromethane to give awhite solid (70, 0.75 g, 70.0%).

Step 2—Synthesis of5-[Hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridine-2-carboxylicacid (4-chloro-phenyl)-amide (71)

To 5-Bromo-pyridine-2-carboxylic acid (4-chloro-phenyl)-amide (70, 0.50g, 1.60 mmol) in tetrahydrofuran (20.0 mL), under an atmosphere ofnitrogen at −78° C., tert-butyllithium (3.02 mL, 1.70 M in Hexane) wasadded. After 20 minutes,1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (47, 0.39g, 1.3 mmol, prepared as described in Example 18) in tetrahydrofuran(10.0 mL) was added to the reaction. The reaction was stirred at −78° C.for 1 hour, then allowed to warm to room temperature for minutes. Thereaction was poured into water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 20% ethyl acetate in hexane to give thecompound as colorless oil (71, 100 mg, 14%). MS (ESI) [M+H⁺]⁺=535.3.

Step 3—Synthesis of5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridine-2-carboxylic acid(4-chloro-phenyl)-amide (P-0076)

To5-[Hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridine-2-carboxylicacid (4-chloro-phenyl)-amide (71, 100.0 mg, 0.19 mmol) in acetonitrile(10.0 mL) were added trifluoroacetic acid (0.20 mL, 2.6 mmol) andtriethylsilane (0.40 mL, 2.5 mmol). The reaction was stirred at 80° C.for 2 hours. The reaction was concentrated and purified by silica gelcolumn chromatography eluting with 20% ethyl acetate in hexane to give ayellow solid compound (P-0076, 5.5 mg, 8.1%).

MS (ESI) [M−H]⁺=361.1.

Example 25 Synthesis of[6-(3-Hydroxy-phenylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0027)

[6-(3-Hydroxy-phenylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0027 was synthesized in 1 Step from[6-(3-Benzyloxy-phenylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0026 as shown in Scheme 27.

To[6-(3-Benzyloxy-phenylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0026, 12.0 mg, 0.0285 mmol) in methanol (5.0 mL) was added 20%palladium hydroxide on carbon (10.0 mg) under an atmosphere of hydrogen.The reaction was stirred at room temperature for 5 hours. Filtration andconcentration gave compound (P-0027, 3.5 mg, 37%). MS (ESI) [M+H⁺]⁺=331.

Example 26 Synthesis of3-[6-(3-Trifluoromethyl-benzyloxy)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridineP-0057

3-[6-(3-Trifluoromethyl-benzyloxy)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridineP-0057 was synthesized in 4 steps from commercially available7-azaindole as shown in Scheme 28.

Step 1—Preparation of(6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (7)

To 7-azaindole 1 in dichloromethane was added 6-chloronicotinoylchloride 8, followed by aluminum chloride, under an atmosphere ofnitrogen at −10° C. The reaction was stirred and allowed to warm to roomtemperature overnight. The reaction was quenched with 3 N hydrochloricacid and concentrated hydrochloric acid was added until all solidsdissolved. The mixture was extracted with dichloromethane and thecombined organic portions were dried with magnesium sulfate, filtered,and the filtrate was concentrated. The resulting solid material wasrecrystallized from chloroform/hexane to provide(6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 7 andused in the next step without further purification.

Step 2—Preparation of(1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-methanone(73)

To (6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 7in DMSO was added (3-trifluoromethyl-phenyl)-methanol 72. Sodium hydridewas added and the reaction was heated to 60° C. for two hours. Thereaction was quenched with water and extracted with ethyl acetate. Theorganic portion was dried with magnesium sulfate and concentrated toprovide(1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-methanone73, which was used in the next step without additional purification.

Step 3—Preparation(1H-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-methanol(74)

To(1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-methanone73 in ethanol was added sodium borohydride. After one hour, the reactionwas quenched with water and extracted with ethyl acetate. The organicportion was dried with magnesium sulfate and concentrated to provide(1H-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-methanol74, which was used in the next step without additional purification.

Step 4—Preparation of3-[6-(3-Trifluoromethyl-benzyloxy)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine,P-0057

(1H-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-methanol74 was dissolved in 9:1 trifluoroacetic acid: triethylsilane. Thereaction was stirred at room temperature for 15 hours. The reaction wasdiluted with water and extracted with ethyl acetate and concentrated.The crude material was purified by reverse phase HPLC to provide3-[6-(3-Trifluoromethyl-benzyloxy)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridineP-0057. MS (ESI) [M+H⁺]⁺=384.3.

Additional compounds may be prepared using steps 2-4 of Scheme 28,replacing (3-trifluoromethyl-phenyl)-methanol with an appropriate benzylalcohol. The following compounds were made following this procedure:

-   3-[6-(4-Chloro-benzyloxy)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine    (P-0056)-   3-[6-(3-Chloro-benzyloxy)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine    (P-0055)    The benzyl alcohols used in step 2 of this procedure are indicated    in column 2 of the following table, with the compound structure    indicated in column 3. Column 1 provides the compound number and    Column 4 the measured mass spectrometry result.

MS(ESI) [M + H⁺]⁺ Benzyl alcohol Compound observed P-0056

350.3 P-0055

350.3

Example 27 Synthesis of[2-Chloro-6-(4-chloro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0048

[2-Chloro-6-(4-chloro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0048 was synthesized in 3 steps from commercially available2,6-dichloropyridine-3-carboxylic acid 75 as shown in Scheme 29.

Step 1—Preparation of 2,6-dichloropyridine-3-carbonyl chloride (76)

To 2,6-dichloropyridine-3-carboxylic acid (75, 1.00 g, 0.00521 mol) indichloromethane (75 mL) was added 2 M Oxalyl chloride (2.61 mL, 0.727 g,0.00573 mol). The solution began to show vigorous gas evolution, whichslowed but continued for about 2 hours. The reaction was allowed tocontinue at room temperature for an additional 3 hours. The reaction wasconcentrated to give the compound as a brown oil that crystallized onstanding (76, 1.09 g, 99%).

Step 2—Preparation of (2,6-dichloropyridin-3-yl)(1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (77)

To Aluminum trichloride (4.18 g, 0.0314 mol) and dichloromethane (97.5mL, 1.52 mol) under an atmosphere of nitrogen was added1H-Pyrrolo[2,3-b]pyridine (1, 828.5 mg, 0.0070 mol) in dichloromethane(5.0 mL). The reaction was stirred at room temperature for 60 minutes,then added 2,6-dichloropyridine-3-carbonyl chloride (76, 1.09 g, 0.00523mol) in dichloromethane (6.0 mL). The reaction was stirred at roomtemperature for 2 hours. A precipitate formed, and nitromethane wasadded in ˜1 mL portions until almost all solid dissolved (8 mL). Afteran additional 60 minutes at room temperature, the reaction was slowlypoured into water and extracted with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate and filtered. The filtratewas concentrated to give 1.54 g of solid, which turned dark purple onsitting overnight. The solid was treated with dichloromethane, and theinsoluble material was collected by vacuum filtration to give compound(77, 863 mg, 57%). MS (ESI) [M+H⁺]⁺=292.2.

Step 3—Preparation of[2-Chloro-6-(4-chloro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyidin-3-yl)-methanone (P-0048)

To (2,6-dichloropyridin-3-yl)(1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(77, 0.0570 g, 0.195 mmol) was added 2-propanol (1.5 mL) followed byp-chlorobenzylamine (61, 49.8 μL, 0.410 mmol). The reaction wasmicrowaved at 300 watts, 100° C. for 10 minutes, at 120° C. for 10minutes, and finally at 150° C. for 10 minutes. Additionalp-chlorobenzylamine (50 μL, 0.410 mmol) was added and the reactioncontinued at 150° C. for 20 minutes. The reaction was extracted withethyl acetate and 1 M sodium bicarbonate. The organic layer was driedover anhydrous magnesium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith dichloromethane followed by 1% methanol to give compound (P-0048,47 mg, 61%). MS (ESI) [M+H⁺]⁺=397.3.

Additional compounds may be prepared according to Scheme 29, replacing2,6-dichloropyridine-3-carboxylic acid with an appropriate carboxylicacid.(6-(4-chlorobenzylamino)-2-(trifluoromethyl)pyridin-3-yl)(1H-pyrrolo[2,3-b]pyridin-3-yl)methanoneP-0070

was made following this protocol, using6-Chloro-2-trifluoromethyl-nicotinic acid as the carboxylic acid(prepared in two steps from commercially available2-chloro-6-(trifluoromethyl)pyridine according to Cottet, F. andSchlosser, M. Eur. J. Org. Chem. 2004, 3793-3798). MS (ESI)[M+H⁺]⁺=431.2.

Example 28 Synthesis of3-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-(4-chlorobenzylamino)pyridin-2-olP-0051

3-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-(4-chlorobenzylamino)pyridin-2-olP-0051 was synthesized in 2 steps from[2-Chloro-6-(4-chloro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyidin-3-yl)-methanoneP-0048 as shown in Scheme 30.

Step 1—Preparation of (6-(4-chlorobenzylamino)-2-chloropyridin-3-yl)(H-pyrrolo[2,3b]pyridin-3-yl)methanol (P-0050)

To[2-Chloro-6-(4-chloro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0048, 0.045 g, 0.00011 mol, prepared as described in Example 27) wasadded methanol (10 mL) and sodium borohydride (0.00428 g, 0.000113 mol).The reaction was allowed to stir at 50° C. overnight. The volatiles wereremoved from the reaction, and the resulting material was extracted withethyl acetate and 1M aqueous sodium bicarbonate. The organic layer wasdried over magnesium sulfate and filtered. The filtrate was concentratedand purified by silica gel column chromatography eluting withdichloromethane followed by 1% methanol in dichloromethane to give thecompound (P-0050, 31 mg, 68%). MS (ESI) [M+H⁺]⁺=399.2.

Step 2—Preparation of3-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-(4-chlorobenzylamino)pyridin-2-ol(P-0051)

To(6-(4-chlorobenzylamino)-2-chloropyridin-3-yl)(1H-pyrrolo[2,3-b]pyridin-3-yl)methanol(P-0050, 0.028 g, 0.000070 mol) dissolved in acetonitrile (1 mL) wasadded triethylsilane (42.6 uL, 0.000266 mol) and trifluoroacetic acid(28.4 uL, 0.000368 mol). The reaction was heated at 85° C. overnight.The reaction was extracted with ethyl acetate and saturated sodiumbicarbonate. The organic layer was separated, dried over magnesiumsulfate and filtered. The filtrate was concentrated and purified bysilica gel column chromatography eluting with dichloromethane, 3%, 5%and finally 10% methanol in dichloromethane to give the compound as awhite solid (P-0051, 20 mg, 78%). MS (ESI) [M+H⁺]⁺=365.3.

Example 29 Synthesis of 5 substituted 7-azaindole intermediates

5-(2-Morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine 79 was synthesizedin 1 Step from commercially available 5-bromo-azaindole as shown inScheme 31.

Step 1—5-(2-Morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine (79)

To 4-morpholineethanol (30 mL, 0.2 mol) in N,N-dimethylformamide (30 mL)was slowly added sodium hydride (7 g, 60% dispersion in mineral oil, 0.2mol). After the solution turned clear, a solution of 5-bromo-7-azaindole(44, 1.0 g, 0.0051 mol) in N,N-dimethylformamide (5 mL) and copper(I)bromide (1.4 g, 0.0098 mol) were added. The reaction mixture was stirredat 120° C. under nitrogen for 2 hours. The reaction mixture wasconcentrated and the residue was dissolved in ethyl acetate and water.The organic layer was collected, washed with a solution of ammoniumchloride and ammonium hydroxide (4:1), brine, and dried over magnesiumsulfate. After removal of solvent, the residue was purified by silicagel column chromatography eluting with ethyl acetate in hexane toprovide the compound as an off-white solid (79, 0.62 g, 50%). MS (ESI)[M+H⁺]⁺=248.25.

Additional 5-substituted 7-azaindoles were prepared following theprotocol of Scheme 31, replacing 4-morpholineethanol with either2-diethylamino-ethanol, 3-diethylamino-propan-1-ol,2-piperidin-1-yl-ethanol, or 2-pyrrolidin-1-yl-ethanol to providediethyl-[2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-ethyl]-amine,Diethyl-[3-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-propyl]-amine,5-(2-piperidin-1-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine, and5-(2-pyrrolidin-1-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine, respectively.

Example 30 Synthesis of{5-[5-(2-Morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-amineP-0065

{5-[5-(2-Morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-amineP-0065 was synthesized in 4 Steps from(5-bromo-pyridin-2-yl)-(4-trifluoromethylbenzyl)-amine 17 as shown inScheme 32.

Step 1—Preparation of6-(4-Trifluoromethyl-benzylamino)-pyridine-3-carbaldehyde (18)

To a solution of (5-bromo-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine(17, 3.55 g, 0.0107 mol, commercially available, or prepared asdescribed in Example 10) in tetrahydrofuran (150 mL) was addedtert-butyllithium (13.2 mL, 1.70 M in pentane, 0.0224 mol) slowly underan atmosphere of nitrogen at −78° C. over 10 minutes. The reactionmixture was stirred at −78° C. for 90 minutes. N,N-Dimethylformamide(2.2 mL, 0.028 mol) was added slowly into the reaction mixture. Thereaction mixture was stirred at −78° C. for 2 hours, then allowed towarm to room temperature. After stirring at room temperature for 2hours, the reaction mixture was poured into ice water and extracted withethyl acetate. The organic phase was washed with saturated sodiumbicarbonate, brine, and dried over magnesium sulfate. After removal ofsolvent, the residue was purified by silica gel column chromatographyeluting with ethyl acetate in hexane to provide the compound as a lightyellow solid (18, 1.67 g, 56%).

Step 2—Preparation of(5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acidtert-butyl ester (19)

To a solution of6-(4-trifluoromethyl-benzylamino)-pyridine-3-carbaldehyde (18, 3.7 g,0.013 mol) and di-tert-butyldicarbonate (3.4 g, 0.016 mol) indichloromethane (100 mL) was added N,N-diisopropylethylamine (4.6 mL,0.026 mol) and 4-diethylaminopyridine (0.2 g, 0.002 mol). The reactionmixture was stirred at room temperature overnight. The reaction mixturewas concentrated and then dissolved in ethyl acetate. The solution waswashed with hydrochloric acid (10%), saturated sodium bicarbonate,brine, and dried over magnesium sulfate. After removal of solvent, theresidue was purified by silica gel column chromatography eluting withethyl acetate in hexane to provide the compound as a white solid (19,4.38 g, 87%).

Step 4—Preparation of(5-{Hydroxy-[5-(2-morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methyl}-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamicacid tert-butyl ester (80)

A mixture of (5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamicacid tert-butyl ester (19, 315 mg, 0.828 mmol),5-(2-morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine (79, 205 mg, 0.829mmol, prepared as described in Example 29), and potassium hydroxide (70mg, 1 mmol) in methanol (25 mL) was stirred at room temperatureovernight. The reaction mixture was poured into ice water, extractedwith ethyl acetate, washed with brine, and dried over sodium sulfate.After removal of solvent, the residue was purified by silica gel columnchromatography eluting with methanol in dichloromethane to provide thecompound as a yellow solid (80, 0.2 g, 40%). MS (ESI) [M+H⁺]⁺=628.42.

Step 5—Preparation of{5-[5-(2-Morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-amine(P-0065)

A mixture of(5-{Hydroxy-[5-(2-morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methyl}-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamicacid tert-butyl ester (80, 0.2 g, 0.3 mmol), triethylsilane (4 mL, 0.02mol), and trifluoroacetic acid (2 mL, 0.02 mol) in acetonitrile (30 mL)was refluxed for 2 hours. After removal of solvent, the residue wasdissolved in ethyl acetate, washed with saturated sodium bicarbonate,brine, and dried over magnesium sulfate. After removal of solvent, theresidue was purified by silica gel column chromatography eluting withmethanol in dichloromethane to provide the compound as a light yellowsolid (P-0065, 17 mg, 10%). MS (ESI) [M+H⁺]⁺=512.42.

Additional compounds may be prepared using steps 3 and 4 of Scheme 32,using (5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acidtert-butyl ester 19 or replacing it with(5-Formyl-pyridin-2-yl)-(4-chloro-benzyl)-carbamic acid tert-butyl ester(43, prepared as described in Example 17) and replacing5-(2-Morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine 79 with anappropriate azaindole, prepared as in Example 29 or5-methoxy-7-azaindole (prepared as described in Example 31) or withcommercially available 5-chloro-7-azaindole. The following compoundswere made following this procedure:

-   [5-(5-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine    (P-0053),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine    (P-0054),-   (4-Chloro-benzyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0058),-   (4-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0059),-   {5-[5-(2-Diethylamino-ethoxy)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-amine    (P-0060),-   (4-Chloro-benzyl)-{5-[5-(2-morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-yl}-amine    (P-0063),-   {5-[5-(2-Pyrrolidin-1-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-amine    (P-0064),-   {5-[5-(3-Diethylamino-propoxy)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-amine    (P-0066),-   (4-Chloro-benzyl)-{5-[5-(3-diethylamino-propoxy)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]pyridin-2-yl}-amine    (P-0069),    The aldehyde and azaindole used in step 4 of this procedure are    indicated in columns 2 and 3 of the following table, respectively,    with the compound structure indicated in column 4. Column 1 provides    the compound reference number and Column 5 the experimental mass    spectrometry result.

MS(ESI) [M + H⁺]⁺ Aldehyde Azaindole Compound observed P-0053

413.2 P-0054

417.2 P-0058

379.2 P-0059

383.2 P-0060

498.4 P-0063

478.3 P-0064

496.3 P-0066

512.3 P-0069

478.3

Example 31 Synthesis of3-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridin-5-olP-0061

3-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridin-5-olP-0061 was synthesized in 6 Steps from 5-bromo-7-azaindole 44 asdescribed in Scheme 33.

Step 1—Preparation of 5-Methoxy-1H-pyrrolo[2,3-b]pyridine (81)

To a mixture of 5-bromo-7-azaindole (1 g, 0.005 mol) inN,N-Dimethylformamide (20 mL) and methanol (20 mL) were added sodiummethoxide (13 g, 0.24 mol) and Copper (I) bromide (0.7 g, 0.0048 mol) atroom temperature. The reaction mixture was stirred at 120° C. undernitrogen for 3 hours. The reaction mixture was concentrated and theresidue was dissolved in ethyl acetate and water. The organic layer wascollected, washed with a solution of ammonium chloride and ammoniumhydroxide (4:1), brine, and dried over magnesium sulfate. After removalof solvent, the residue was purified by silica gel column chromatographyeluting with ethyl acetate in hexane to provide the compound as a whitesolid (81, 0.4 g, 50%). MS (ESI) [M+H⁺]⁺=149.09.

Step 2—Preparation of 1H-Pyrrolo[2,3-b]pyridin-5-ol (82)

To a solution of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (81, 0.5 g, 3 mmol)in tetrahydrofuran (20 mL) was added boron tribromide (1.5 g, 6.0 mmol)at 0° C. The reaction mixture was allowed to warm to room temperature,then stirred at room temperature for 3 hours. The reaction mixture wasquenched by methanol. After repeated addition of methanol and removal ofsolvent, the concentrated reaction mixture was dissolved in ethylacetate and water. The organic layer was collected, washed with brine,and dried over magnesium sulfate. After removal of solvent, the residuewas purified by silica gel column chromatography eluting with ethylacetate in hexane to provide the compound as an off-white solid (82,0.18 g, 40%).

Step 3—Preparation of 5-Triisopropylsilanyloxy-1H-pyrrolo[2,3-b]pyridine(83)

To a solution of 1H-Pyrrolo[2,3-b]pyridin-5-ol (0.5 g, 0.004 mol) and1H-imidazole (0.98 g, 0.014 mol) in N,N-dimethylformamide (5 mL) wasadded triisopropylsilyl chloride (1 mL, 0.005 mol). The reaction mixturewas stirred at room temperature overnight. Dichloromethane (10 mL) wasadded and the solution was washed with brine and dried over sodiumsulfate. After removal of solvent, the residue was purified by silicagel column chromatography eluting with ethyl acetate in hexane toprovide the compound as a viscous liquid (83, 0.4 g, 40%).

Step 4—Preparation of{5-[Hydroxy-(5-triisopropylsilanyloxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-carbamicacid tert-butyl ester (84)

A mixture of (5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamicacid tert-butyl ester (19, 41 mg, 0.11 mmol, prepared as described inExample 30), 5-triisopropylsilanyloxy-1H-pyrrolo[2,3-b]pyridine (83, 34mg, 0.12 mmol) and potassium hydroxide (9.8 mg, 0.17 mmol) in methanol(10 mL) was stirred at room temperature overnight. The reaction mixturewas poured into water, extracted with ethyl acetate, washed with brineand dried over sodium sulfate. After removal of solvent, the residue waspurified by silica gel column chromatography eluting with ethyl acetatein hexane to provide the compound as a viscous liquid (84, 0.05 g, 70%).MS (ESI) [M+H⁺]⁺=671.38.

Step 5—Preparation of(4-Trifluoromethyl-benzyl)-[5-(5-triisopropylsilanyloxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(85)

A mixture of{5-[hydroxy-(5-triisopropylsilanyloxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-carbamicacid tert-butyl ester (84, 0.05 g, 0.07 mmol), trifluoroacetic acid (0.5mL, 0.006 mol), and triethylsilane (1 mL, 0.006 mol) in acetonitrile (10mL) was refluxed for 2 hours. The reaction mixture was poured into icewater, extracted with ethyl acetate, washed with saturated sodiumbicarbonate, brine, and dried over sodium sulfate. After removal ofsolvent, the residue was purified by silica gel column chromatographyeluting with ethyl acetate in hexane to provide the compound as aviscous liquid (85, 0.04 g, 97%). MS (ESI) [M+H⁺]⁺=555.38.

Step 6—Preparation of3-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridin-5-ol(P-0061)

To(4-Trifluoromethyl-benzyl)-[5-(5-triisopropylsilanyloxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(85, 0.13 g, 0.23 mmol) in tetrahydrofuran (10 mL) was addedtetrabutylammonium fluoride (3 mL, 1.0 M in tetrahydrofuran, 3 mmol).The reaction mixture was stirred at room temperature overnight, and thenwas stirred at 65° C. for 48 hours. The reaction mixture wasconcentrated and purified by silica gel column chromatography elutingwith ethyl acetate in hexane to provide the compound as a viscous liquid(P-0061, 0.062 g, 66%). MS (ESI) [M+H⁺]⁺=399.19.

3-[6-(4-Chloro-benzylamino)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridin-5-olP-0062

was prepared following the protocol of Scheme 33, replacing(5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acidtert-butyl ester 19 with(5-Formyl-pyridin-2-yl)-(4-chloro-benzyl)-carbamic acid tert-butyl ester(43, prepared as described in Example 17). MS (ESI) [M+H⁺]⁺=365.2.

Example 32 Synthesis ofN-[5-(1H-Pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-4-trifluoromethyl-benzamideP-0067

N-[5-(1H-Pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-4-trifluoromethyl-benzamideP-0067 was synthesized in 2 Steps from 7-azaindole 1 as described inScheme 34.

Step 1—Preparation of(6-Bromo-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (87)

To a solution of 1H-Pyrrolo[2,3-b]pyridine (1, 1.2 g, 0.010 mol) indichloromethane (50 mL) was added 6-bromo-nicotinoyl chloride (86, 2.6g, 0.012 mol) at −10° C. After the solution turned clear, aluminumtrichloride (10.2 g, 0.0765 mol) was added in one portion with vigorousstirring. The reaction mixture was stirred at −10° C. for 30 minutes,then was allowed to warm to room temperature and stirred at roomtemperature overnight. The reaction was quenched with ice water andneutralized with sodium bicarbonate. The solution was extracted withdichloromethane, washed with brine, and dried over sodium sulfate. Afterremoval of solvent, the residue was purified by silica gel columnchromatography eluting with methanol in dichloromethane to provide thecompound as a white solid (87, 0.35 g, 11%).

Step 2—Preparation ofN-[5-(1H-Pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-4-trifluoromethyl-benzamide(P-0067)

A mixture of(6-bromo-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (87,160 mg, 0.53 mmol), 4-trifluoromethyl benzamide (51, 130 mg, 0.69 mmol),xanthphos (9 mg, 0.02 mmol), cesium carbonate (245 mg, 0.752 mmol), andtris(dibenzylideneacetone)dipalladium (0) (5 mg, 0.005 mmol) in toluene(2 mL) in a sealed tube was stirred at 110° C. for 1 hour. The reactionwas quenched with water and extracted with dichloromethane. The organiclayer was collected, washed with brine and dried over sodium sulfate.After removal of the solvent, the residue was purified with silica gelcolumn chromatography eluting with ethyl acetate in hexane to providethe compound as an off-white solid (P-0067, 0.42 mg, 19%). MS (ESI)[M+H⁺]⁺=411.17.

N-[5-(1H-Pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-4-trifluoromethyl-benzenesulfonamideP-0068

was prepared following the protocol of Scheme 34, replacing4-trifluoromethyl benzamide 51 with 4-trifluoromethyl-benzenesulfonamidein Step 2. MS (ESI) [M+H]⁺=445.1.

Example 33 Synthesis of[(S)-1-(4-Chloro-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0075

[(S)-1-(4-Chloro-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0075 was synthesized in 3 Steps from 7-azaindole 1 as described inScheme 35.

Step 1—Preparation of(6-Bromo-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (89)

A mixture of 1H-Pyrrolo[2,3-b]pyridine (1, 1.2 g, 0.010 mol),6-bromo-pyridine-3-carbaldehyde (88, 1.8 g, 0.0097 mol), and potassiumhydroxide (1.8 g, 0.032 mol) in methanol (25 mL) was stirred at roomtemperature overnight. The reaction mixture was poured into ice water,extracted with ethyl acetate, washed with brine, and dried over sodiumsulfate. After removal of solvent, the residue was purified by silicagel column chromatography eluting with methanol in dichloromethane toprovide the compound as a white solid (89, 1.4 g, 45%), or may be usedas mixture of 89 and 90 in Step 2.

Step 2—Preparation of3-(6-Bromo-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (91)

A mixture of(6-bromo-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (89, 1g, 0.003 mol) and3-[(6-bromo-pyridin-3-yl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine (90,2 g, 0.006 mol), triethylsilane (1 mL, 0.006 mol), and trifluoroaceticacid (0.5 mL, 0.006 mol) in acetonitrile (25 mL) was refluxed for 2hours. The reaction mixture was concentrated and the residue wasdissolved in ethyl acetate and water. The organic layer was collected,washed with saturated sodium bicarbonate, brine, and dried over sodiumsulfate. After removal of the solvent, the residue was purified withsilica gel column chromatography eluting with ethyl acetate in hexane toprovide the compound as an off-white solid (91, 0.75 g, 60%). MS (ESI)[M+H⁺]⁺=288.06, 290.00.

Step 3—Preparation of[(S)-1-(4-Chloro-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0075

A mixture of 3-(6-bromo-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(91, 100 mg, 0.0003 mol) and (S)-1-(4-chloro-phenyl)-ethylamine (92, 0.5g, 0.003 mol) in N-methylpyrrolidine (3 mL) was stirred at 150° C. inmicrowave for 100 minutes. The reaction mixture was concentrated undervacuum and the residue was purified with silica gel columnchromatography eluting with ethyl acetate in hexane to provide thecompound as a white solid (P-0075, 0.03 g, 20%). MS (ESI)[M+H⁺]⁺=363.18.

Example 34 Synthesis of(4-Chloro-benzyl)-[4-chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amineP-0083

(4-Chloro-benzyl)-[4-chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amineP-0083 was synthesized in 4 steps from2,4-Dichloro-thiazole-5-carbaldehyde 93 as described in Scheme 36.

Step 1—Preparation of4-Chloro-2-(4-chloro-benzylamino)-thiazole-5-carbaldehyde (94)

To a solution of p-chlorobenzylamine (61, 283 mg, 2.00 mmol) andN,N-Diisopropylethylamine (0.697 mL) in tetrahydrofuran (20 mL) wasslowly added 2,4-Dichloro-thiazole-5-carbaldehyde (93, 364 mg, 2.00mmol) in tetrahydrofuran (10 mL) at room temperature. The reaction wasstirred at room temperature overnight. The reaction mixture was pouredinto iced water, extracted with ethyl acetate, washed with brine, anddried over sodium sulfate. After removal of solvent, the residue waspurified by silica gel column chromatography eluting with ethyl acetatein hexane to provide the compound as a yellow solid (94, 0.3 g, 50%). MS(ESI) [M−H+]=286.97.

Step 2—Preparation of(4-Chloro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acidtert-butyl ester (95)

To a solution of4-Chloro-2-(4-chloro-benzylamino)-thiazole-5-carbaldehyde (94, 0.32 g,0.0011 mol) in dichloromethane (20 mL) was slowly addedN,N-diisopropylethylamine (0.4 mL, 0.002 mol), 4-dimethylaminopyridine(27 mg, 0.22 mmol), and a solution of di-tert-butyldicarbonate (290 mg,0.0013 mol) in dichloromethane (5 mL) at room temperature. The reactionmixture was stirred at room temperature overnight, then poured into icedwater, extracted with dichloromethane, washed with brine, and dried oversodium sulfate. After removal of solvent, the residue was purified bysilica gel column chromatography eluting with ethyl acetate in hexane toprovide the compound as a light brown solid (95, 0.32 g, 74%). MS (ESI)[M+H+]+=387.26.

Step 3—Preparation of(4-Chloro-benzyl)-{4-chloro-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-thiazol-2-yl}-carbamicacid tert-butyl ester (97)

To a solution of 3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(96, 99 mg, 0.25 mmol) in tetrahydrofuran (5 ml) at −20° C. undernitrogen was added 2.0 M solution isopropylmagnesium chloride intetrahydrofuran (0.2 ml, 0.31 mmol). The reaction mixture was stirredfor 1.5 hours, then allowed to warm to 5° C. After the reaction mixturewas cooled down to −20° C., a solution of(4-Chloro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acidtert-butyl ester (95, 80 mg, 0.2 mmol) in tetrahydrofuran (5 mL) wasslowly added. The reaction mixture was stirred for 2.5 hrs, then allowedto warm to 5° C. The reaction mixture was poured into iced water,extracted with ethyl acetate, washed with brine, and dried overmagnesium sulfate. After removal of solvent, the residue was purified bysilica gel column chromatography eluting with ethyl acetate in hexane toprovide the compound as an off-white solid (97, 76 mg, 50%). MS (ESI)[M+H+]+=661.32, 663.32.

Step 4—Preparation of(4-Chloro-benzyl)-[4-chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine(P-0083)

A mixture of(4-Chloro-benzyl)-{4-chloro-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-thiazol-2-yl}-carbamicacid tert-butyl ester (97, 76 mg, 0.11 mmol), triethylsilane (0.5 mL, 3mmol), and trifluoroacetic acid (0.25 mL, 3.2 mmol) in acetonitrile (5mL) was refluxed for 3 hours. The reaction mixture was poured into icedwater, extracted with ethyl acetate, washed with sodium bicarbonate,brine, and dried over sodium sulfate. After removal of solvent, theresidue was purified by silica gel column chromatography eluting withethyl acetate in hexane to provide the compound as a yellow solid(P-0083, 5.6 mg, 14%). MS (ESI) [M+H+]+=389.35, 390.36.

Example 35 Synthesis of[2-(4-Chloro-benzylamino)-thiazol-5-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0077

[2-(4-Chloro-benzylamino)-thiazol-5-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0077 was synthesized in 2 steps from 2-Bromo-thiazole-5-carboxylicacid 98 and 1H-pyrrolo[2,3-b]pyridine 1 as shown in Scheme 37.

Step 1—Preparation of(2-Bromo-thiazol-5-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (99)

A suspension of 2-Bromo-thiazole-5-carboxylic acid (98, 0.5 g, 0.002mol) in oxalyl chloride (3 mL) was stirred at room temperature until itturned into a clear solution. Solvent was removed and the residue wasdried over vacuum. A light yellow solid was obtained and was dissolvedin dichloromethane (10 mL) and slowly added to a solution of1H-Pyrrolo[2,3-b]pyridine (1, 0.34 g, 0.0029 mol) in dichloromethane (30mL) at −10° C. To the mixture was then added aluminum trichloride (2.6g, 0.019 mol) in one portion with vigorous stirring. The reaction washeld at −10° C. for 30 minutes, then allowed to warm to roomtemperature. The reaction mixture was stirred at ambient temperatureovernight. The reaction was quenched with ice-water and acidified withhydrochloric acid (10%) to pH 4. The solution was then extracted withdichloromethane. The organic layer was collected, washed with brine, anddried over magnesium sulfate. After removal of solvent, the residue waspurified by silica gel column chromatography eluting with ethyl acetatein hexane to provide the compound as a white solid (99, 12 mg, 2%). MS(ESI) [M−H+]=369.09.

Step 2—Preparation of[2-(4-Chloro-benzylamino)-thiazol-5-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0077)

A mixture of(2-Bromo-thiazol-5-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (99, 5mg, 0.02 mmol), p-chlorobenzylamine (61, 10 mg, 0.08 mmol), andN,N-Diisopropylethylamine (10 L, 0.08 mmol) in tetrahydrofuran (10 mL),in a sealed reaction vessel, was stirred room temperature overnight. Thereaction mixture was poured into iced water, extracted with ethylacetate, washed with brine, and dried over magnesium sulfate. Afterremoval of solvent, the residue was purified by silica gel columnchromatography eluting with ethyl acetate in hexane to provide thecompound as a light yellow solid (P-0077, 2 mg, 30%). MS (ESI)[M+H+]=305.90, 307.88.

Example 36 Synthesis of3-((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridineP-0080

3-((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridineP-0080 was synthesized in 2 steps from5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde 100 and7-azaindole 1 as shown in Scheme 38.

Step 1—Preparation of 3-((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)(methoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (P-0079)

To 1H-Pyrrolo[2,3-b]pyridine (1, 0.100 g, 0.846 mmol) and5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (100, 0.205 g,0.931 mmol) was added 2 mL of methanol to give a solution. Potassiumhydroxide (0.0475 g, 0.846 mmol) was added and the reaction was allowedto stir at room temperature for 48 hours. The reaction was extractedwith ethyl acetate and water. The organic layer was dried over anhydrousmagnesium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with a gradient of0-5% methanol in dichloromethane to give the compound (P-0079, 32 mg,11%). MS (ESI) [M+H⁺]⁺=353.2.

Step 2—Preparation of3-((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridine(P-0080)

To3-((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)(methoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(P-0079, 0.030 g, 0.085 mmol) was added acetonitrile (10 mL, 0.2 mol).Trifluoroacetic acid (500 uL, 0.006 mol) and triethylsilane (500 uL,0.003 mol) were added and the reaction allowed to stir at roomtemperature for 16 hours. The reaction was extracted with ethyl acetateand water. The organic layer was dried over anhydrous magnesium sulfateand filtered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with dichloromethane followed 5% methanolin dichloromethane to give the compound as a yellowish foam (P-0080, 29mg, 98%).

MS (ESI) [M+H⁺]⁺=323.2.

Example 37 cKit Kinase Domain and Construction of c-Kit sequences

c-Kit cDNA sequence is available from NCBI, e.g., as GenBank accessionnumber NM_(—)000222. Using this sequence, c-kit DNA sequences can becloned from commercially available libraries (e.g. cDNA libraries) orcan be synthesized by conventional cloning methods.

Using conventional cloning methods, constructs encoding three c-kitpolypeptides were prepared, and used to express c-kit kinase domainpolypeptides. One such active c-kit kinase domain sequence includedresidues P551-S948, with the deletion of residues Q694-T753.

Example 38 Expression and Purification of c-Kit Kinase Domain

Purified c-kit kinase domain can be obtained using conventionalexpression and purification methods. Exemplary methods are described,for example, in Lipson et al., U.S. 20040002534 (U.S. application Ser.No. 10/600, 868, filed Jun. 23, 2003), which is incorporated herein byreference in its entirety.

Example 39 Binding Assays

Binding assays can be performed in a variety of ways, including avariety of ways known in the art. For example, as indicated above,binding assays can be performed using fluorescence resonance energytransfer (FRET) format, or using an AlphaScreen.

Alternatively, any method which can measure binding of a ligand to theATP-binding site can be used. For example, a fluorescent ligand can beused. When bound to c-kit, the emitted fluorescence is polarized. Oncedisplaced by inhibitor binding, the polarization decreases.

Determination of IC₅₀ for compounds by competitive binding assays. (Notethat K_(I) is the dissociation constant for inhibitor binding; K_(D) isthe dissociation constant for substrate binding.) For this system, theIC50, inhibitor binding constant and substrate binding constant can beinterrelated according to the following Formula:

When using radiolabeled substrate

${K_{1} = \frac{{IC}\; 50}{1 + {\left\lbrack L^{*} \right\rbrack/K_{D}}}},$

the IC₅₀˜K₁ when there is a small amount of labeled substrate.

Example 40 Cell-Based Assays of c-Fms Kinase Activity or c-Kit KinaseActivity

M-CSF dependent RAW264.7 cells were seeded on a 12 well plate, 2.5×10⁵cells/well and the cells were allowed to attach overnight at 37° C., 5%CO₂. The cells were then starved in serum-free medium overnight at 37°C., 5% CO₂. The cells were treated with compound for 1 hour inserum-free media (1% DMSO final concentration); and then stimulated with20 ng/ml M-CSF for 5 minutes. After stimulation, the cells were lysed onice, and the lysates were centrifuged at 13,000 rpm for 1 minute. Theamount of protein in the sample was quantitated, sample buffer wasadded, and the samples were boiled at 95° C. for minutes. The sampleswere then centrifuged at 13,000 rpm for 1 minute. The samples (15-20μg/lane) were loaded and run on 4-12% tris-glycine gel at 75V, and thentransferred onto a PVDF membrane. The membrane was blocked for 1 hourwith 5% BSA in PBS/1% Tween-20 (PBST); or 5% milk, depending on theprimary antibody used. Then the blots were incubated with primaryantibody overnight at 4 degrees with gentle shaking. After incubationwith the capture antibody, the membranes were washed 3×10 minutes withPBST; then incubated with detection antibody Goat Anti-Rabbit-HRP for 1hour, with gentle shaking. The membranes were washed again 3×10 minuteswith PBST. ECL Plus substrate was then added to the blots, the imagecaptured with chemiluminescence camera, and the bands quantitated forpFMS and FMS levels.

The Fms inhibitors may also be assessed using M-NFS-60 mouse myelogenousleukemia cell line (ATCC catalog #CRL-1838). This cell lineproliferation is stimulated by M-CSF, which binds and activates the finstyrosine kinase receptor. Inhibitors of fins kinase activity reduce oreliminate the M-CSF stimulated kinase activity, resulting in reducedcell proliferation. This inhibition is measured as a function ofcompound concentration to assess IC₅₀ values. M-NFS-60 cells were seededat 5×10⁴ cells per well of a 96 well cell culture plate in 50 μl of cellculture medium of RPMI 1640 (CellGro Mediatech catalog #10-040-CV)supplemented with 10% FBS (HyClone catalog #SH30071.03). Compounds weredissolved in DMSO at a concentration of 1 mM and were serially diluted1:3 for a total of eight points and added to the cells to finalconcentrations of 10, 3.3, 1.1, 0.37, 0.12, 0.041, 0.014 and 0.0046 μMin 100 μl cell culture medium (final concentration 0.2% DMSO). Cellswere also treated with staurosporine as a positive control. The cellswere stimulated by adding 20 μl of 372 ng/ml M-CSF to a finalconcentration of 62 ng/ml (R&D Systems catalog #216-MC). The cells wereincubated at 37° C., 5% CO₂ for three days. CellTiter-Glo Buffer(Promega Cell Viability Assay catalog #G7573) and substrate wereequilibrated to room temperature, and enzyme/substrate RecombinantFirefly Luciferase/Beetle Luciferin was reconstituted. The cell plateswere equilibrated to room temperature for 30 minutes, then lysed byaddition of an equivalent volume of the Celltiter-Glo Reagent. The platewas mixed for 2 minutes on a plate shaker to lyse the cells, thenincubated for 10 minutes at room temperature. The plates were read on aVictor Wallac II using Luminescence protocol modified to read 0.1s perwell. The luminescence reading assesses the ATP content, whichcorrelates directly with cell number such that the reading as a functionof compound concentration was used to determine the IC₅₀ value.

The c-Kit inhibitors were assessed using M-07e cell line (DSMZ catalog#ACC 104). The M-07e proliferation is stimulated by SCF (Stem CellFactor), which binds and activates c-Kit tyrosine kinase receptor.Inhibitors of c-Kit kinase reduce or eliminate the SCF mediated kinaseactivation, resulting in reduced cell proliferation of SCF stimulatedcells. This inhibition is measured by the effect of compoundconcentration on cell growth to assess IC₅₀ values. M-07e cells wereseeded at 5×10⁴ cells per well of a 96 well cell culture plate in 50 μlof cell culture medium of Iscove's Medium 1×(MOD, CellGro Mediatechcatalog #15-0,6-CV) supplemented with 10% FBS (HyClone catalog#SH30071.03). Compounds were dissolved in DMSO at a concentration of 0.1mM and were serially diluted 1:3 for a total of eight points and addedto the cells to final concentrations of 1, 0.33, 0.11, 0.037, 0.012,0.0041, 0.0014 and 0.00046 μM in 100 μl cell culture medium (finalconcentration 0.2% DMSO). Cells were also treated with staurosporine asa positive control. Cells were stimulated by adding 20 μl of 600 ng/mlSCF to a final concentration of 100 ng/ml (Biosource International SCFkit ligand catalog #PHC2115) in cell culture medium. The cells wereincubated at 37° C., 5% CO₂ for three days. CellTiter-Glo Buffer(Promega Cell Viability Assay catalog #G7573) and substrate wereequilibrated to room temperature, and enzyme/substrate RecombinantFirefly Luciferase/Beetle Luciferin was reconstituted. The cell plateswere equilibrated to room temperature for 30 minutes, then lysed byaddition of an equivalent volume of the Celltiter-Glo Reagent. The platewas mixed for 2 minutes on a plate shaker to lyse the cells, thenincubated for 10 minutes at room temperature. The plates were read on aVictor Wallac II using Luminescence protocol modified to read 0.1s perwell. The luminescence reading assesses the ATP content, whichcorrelates directly with cell number such that the reading as a functionof compound concentration is used to determine the IC₅₀ value.

This cell based assay was also used to assess phosphorylation. Sampleswere prepared with compounds as described for the growth inhibitionassay only M-07e cells were seeded at 2×10⁵ cells per well in a 96 wellfilter plate. Cells were incubated for 1 hour at 37° C. with thecompounds as described above, and then stimulated by adding SCF to afinal concentration of 50 ng/ml and incubated for 10 minutes at 37° C.The culture medium was removed by centrifugation and the cells werelysed by addition of 30 μl lysis buffer (25 mM Tris HCl pH 7.5, 150 mMNaCl, 5 mM EDTA, 1% Triton X100, 5 mM NaF, 1 mM NaVanadate, 10 mMBeta-glycerophosphate, no EDTA (Boehringer-Roche catatalog #1873580) andplaced on ice for 30 minutes. A 15 μl aliquot of the lysate was takenand assayed according to Biosource Immunoassay Kit: Human c-Kit[pY823](Catalog #KHO0401) by diluting the aliquot with 85 μl dilutionbuffer in the assay plate, incubating for 2 hours at room temperatureand washing the plate 4 times with wash buffer. Detection antibody (100μl) was added to the plate and samples incubated for 1 hour at roomtemperature, then washed 4 times with wash buffer. HRP anti-rabbitantibody (100 μl) was added and samples incubated for 30 minutes at roomtemperature, then washed 4 times with wash buffer. Stabilized chromogen(100 μl) was added and samples incubated for 15-25 minutes at roomtemperature, then washed 4 times with wash buffer. Stop solution (100μl) was added and the samples read on a Wallac Victor reader at 450 nm.The absorbance was plotted against the compound concentration and theIC₅₀ concentration was determined.

Additional cell based assays can be correlated to the Fms activity ofcompounds of the invention. For example, the ability of osteoclastprecursor cells (commercially available from Lonza) to differentiateinto mature osteoclasts, due to stimulation by M-CSF and RANKL, in thepresence of compounds, can be measured using a method analogous to thatpreviously reported (Hudson et al., Journal of Urology, 1947, 58:89-92),where the amount of acid phosphatase in the supernatant (i.e. TRAP5bexcreted by mature osteoclasts) is proportional to the number of matureosteoclasts present. In another example, the ability of M-CSF-dependentmurine macrophage cells (BAC 1.2F5) to proliferate in the presence ofcompounds can be measured by culturing cells as previously described(Morgan et al., Journal of Cellular Physiology, 1987, 130:420-427) anddetermining cell viability by analysis of ATP levels in the cell culture(Crouch et al., Journal of Immunological Methods, 1993, 160:81-8).

Example 41 c-Kit, c-Fms, TrkA, and HGK Activity Assays

The effect of potential modulators of kinase activity of c-kit and otherkinases can be measured in a variety of different assays known in theart, e.g., biochemical assays, cell-based assays, and in vivo testing(e.g. model system testing). Such in vitro and/or in vivo assays andtests can be used in the present invention. As an exemplary kinaseassay, the kinase activity of c-kit or Fms is measured in AlphaScreening(Packard BioScience).

Exemplary c-kit Biochemical Assay

The c-kit (or kinase domain thereof) is an active kinase in AlphaScreen.IC₅₀ values are determined with respect to inhibition of c-Kit kinaseactivity, where inhibition of phosphorylation of a peptide substrate ismeasured as a function of compound concentration. Compounds to be testedwere dissolved in DMSO to a concentration of 20 mM. These were diluted30 μl into 120 μl of DMSO (4 mM) and 1 μl was added to an assay plate.These were then serially diluted 1:3 (50 μl to 100 μl DMSO) for a totalof 8 points. Plates were prepared such that each kinase reaction is 20μl in 1× kinase buffer (50 mM HEPES, pH 7.2, 5 mM MgCl₂, 5 mM MnCl₂,0.01% NP-40, 0.2% BSA), 5% DMSO and 10 μM ATP. Substrate was 100 nMbiotin-(E4Y)₃ (Open Source Biotech, Inc.). C-kit kinase was at 0.1 ngper sample. After incubation of the kinase reaction for 1 hour at roomtemperature, 5 μl of donor beads (Streptavidin coated beads (PerkinElmer Life Science) final concentration 1 μg/ml) in stop buffer (50 mMEDTA in 1× kinase buffer) was added, the sample was mixed and incubatedfor minutes at room temperature before adding 5 μl of acceptor beads(PY20 coated beads (Perkin Elmer Life Science) final concentration 1μg/ml) in stop buffer. The samples were incubated for 60 minutes at roomtemperature and the signal per well was read on AlphaQuest reader.Phosphorylated substrate results in binding of the PY20 antibody andassociation of the donor and acceptor beads such that signal correlateswith kinase activity. The signal vs. compound concentration was used todetermine the IC₅₀.

Compounds were also tested using a similar assay with a 10-fold higherATP concentration. For these samples, compounds to be tested weredissolved in DMSO to a concentration of 20 mM. These were diluted 30 μlinto 120 μl of DMSO (4 mM) and 1 μl was added to an assay plate. Thesewere then serially diluted 1:3 (50 μl to 100 μl DMSO) for a total of 8points. Plates were prepared such that each kinase reaction is 20 μl in1× kinase buffer (25 mM HEPES, pH 7.5, 2 mM MgCl₂, 2 mM MnCl₂, 0.01%Tween-20, 1 mM DTT, and 0.001% BSA), 5% DMSO and 100 μM ATP. Substratewas 30 nM biotin-(E4Y)10 (Upstate Biotech, Cat#12-440). C-kit kinase wasat 1 ng per sample. After incubation of the kinase reaction for 1 hourat room temperature, 5 μl of donor beads (Streptavidin coated beads(Perkin Elmer Life Science) final concentration 10 μg/ml) in stop buffer(25 mM HEPES pH 7.5, 100 mM EDTA, 0.3% BSA) was added, the sample wasmixed and incubated for 20 minutes at room temperature before adding 5μl of acceptor beads (PY20 coated beads (Perkin Elmer Life Science)final concentration 10 μg/ml) in stop buffer. The samples were incubatedfor 60 minutes at room temperature and the signal per well was read onAlphaQuest or Envision reader (Perkin Elmer Life Science).Phosphorylated substrate results in binding of the PY20 antibody andassociation of the donor and acceptor beads such that signal correlateswith kinase activity. The signal vs. compound concentration was used todetermine the IC₅₀.

The c-kit enzyme used in the above assay was either obtained from CellSignaling Technology (Cat. #7754) or was prepared as follows: A plasmidencoding kit (DNA and encoded protein sequences shown below) wasengineered using common polymerase chain reaction (PCR) methods.Complementary DNA cloned from various human tissues were purchased fromInvitrogen, and these were used as substrates in the PCR reactions.Specific custom synthetic oligonucleotide primers were designed toinitiate the PCR product, and also to provide the appropriaterestriction enzyme cleavage sites for ligation with the plasmids. Theentire sequence encoding the enzyme was made through a gene synthesisprocedure, using custom synthetic oligonucleotides covering the entirecoding sequence (Invitrogen, see below).

The plasmid used for ligation with the kinase-encoding inserts wasderivative of pET (Novagen) for expression using E. coli. The Kit kinasewas engineered to include a Histidine tag for purification using metalaffinity chromatography. The kinase-encoding plasmid was engineered asbicistronic mRNA to co-express a second protein that modifies the kinaseprotein during its expression in the host cell. Protein tyrosinephosphatase 1B (PTP), was co-expressed for dephosphorylation of thephospho-Tyrosines.

For protein expression, the plasmid containing the Kit gene wastransformed into E. coli strains BL21(DE3)RIL and transformants selectedfor growth on LB agar plates containing appropriate antibiotics. Singlecolonies were grown overnight at 37° C. in 200 ml TB (Terrific broth)media. 16×1 L of fresh TB media in 2.8 L flasks were inoculated with 10ml of overnight culture and grown with constant shaking at 37° C. Oncecultures reached an absorbance of 1.0 at 600 nm, IPTG was added andcultures were allowed to grow for a further 12 to 18 hrs at temperaturesranging from 12-30° C. Cells were harvested by centrifugation andpellets frozen at −80° C. until ready for lysis.

For protein Purification; frozen E. coli cell pellets were resuspendedin lysis buffer and lysed using standard mechanical methods. Protein waspurified via poly-Histidine tags using immobilized metal affinitypurification IMAC. The Kit kinase was purified using a 3 steppurification process utilizing; IMAC, size exclusion chromatography andion exchange chromatography. The poly-Histidine tag was removed usingThrombin (Calbiochem).

Compounds were assayed using a similar assay to that described above,using in a final reaction volume of 25 μl: c-Kit (h) (5-10 mU) in 8 mMMOPS pH 7.0, 0.2 mM EDTA, mM MnCl₂, 0.1 mg/ml poly (Glu, Tyr) 4:1, 10 mMMgAcetate and γ- ³³P-ATP (approximately 500 cpm/pmol), with appropriateconcentrations of compound. Incubated for minutes at room temperatureand stopped by addition of 5 μl of 3% phosphoric acid. Spotted 10 μl ofeach sample onto Filtermat A and washed 3× with 75 mM phosphoric acid,once with methanol, dried and measured on scintillation counter(performed at Upstate USA, Charlottesville, Va.).

Compounds P-0001, P-0002, P-0003, P-0004, P-0005, P-0006, P-0007,P-0008, P-0009, P-0010, P-0011, P-0012, P-0013, P-0014, P-0015, P-0016,P-0017, P-0018, P-0020, P-0022, P-0024, P-0025, P-0026, P-0027, P-0028,P-0030, P-0031, P-0032, P-0033, P-0038, P-0053, P-0054, P-0055, P-0056,P-0057, P-0058, P-0059, P-0060, P-0061, P-0062, P-0063, P-0064, P-0065,P-0066, P-0069, P-0071, P-0072, P-0073, P-0074, P-0075, P-0078, P-0082,P-0092, P-0093, P-0094, P-0095, P-0096, P-0097, P-0098, P-0099, P-0100,P-0101, P-0102, P-0103, P-0104, P-0105, P-0107, P-0108, P-0109, P-0111,P-0112, P-0113, P-0114, P-0115, P-0116, P-0118, P-0120, P-0121, P-0122,P-0123, P-0125, P-0126, P-0127, P-0128, P-0129, P-0131, P-0132, P-0138,P-0143, P-0144, P-0145, P-0148, P-0154, P-0156, P-0157, P-0159, P-0161,P-0163, P-0170, P-0171, P-0173, P-0174, P-0176, P-0177, P-0179, P-0180,P-0181, P-0182, P-0186, P-0187, P-0188, P-0190, P-0192, P-0193, P-0194,P-0195, P-0197, P-0199, P-0201, P-0203, P-0205, P-0206, P-0208, P-0211,P-0212, P-0213, P-0214, P-0215, P-0216, P-0217, P-0218, P-0219, P-0221,P-0222, P-0224, P-0225, P-0226, P-0228, P-0234, P-0237, P-0239, P-0240,P-0242, P-0243, P-0244, P-0245, P-0246, P-0252, P-0253, P-0255, P-0257,P-0258, P-0259, P-0260, P-0262, P-0263, P-0264, P-0265, P-0266, P-0267,P-0268, P-0269, P-0270, P-0271, P-0272, P-0273, P-0274, P-0275, P-0276,P-0277, P-0278, P-0279, P-0280, P-0281, P-0282, P-0283, P-0284, P-0285,P-0286, P-0287, P-0288, P-0289, P-0290, P-0291, P-0294, P-0297, P-0298,P-0301, P-0302, P-0303, P-0305, P-0306, P-0307, P-0308, P-0309, P-0311,P-0312, P-0313, P-0314, P-0316, P-0319, P-0320, P-0321, P-0322, P-0323,P-0324, P-0325, P-0326, P-0327, P-0328, P-0329, P-0330, P-0331, P-0332,P-0334, P-0336, P-0337, P-0338, P-0339, P-0340, P-0341, P-0342, P-0343,P-0344, P-0345, P-0346, P-0347, P-0348, P-0350, P-0351, P-0352, P-0354,P-0355, P-0356, P-0357, P-0358, P-0359, P-0361, P-0362, P-0363, P-0365,P-0366, P-0367, P-0368, P-0369, P-0370, P-0371, P-0372, P-0373, P-0375,P-0376, P-0377, P-0378, P-0379, P-0382, P-0383, P-0385, P-0387, P-0390,P-0392, P-0393, P-0394, P-0395, P-0396, P-0402, P-0404, P-0406, P-0407,P-0408, P-0409, and P-0412 had IC₅₀ of less than 1 μM in at least one ofthe c-kit assays described above in Examples 40 and 41.

Kit PCR primers KIT 8K1A ATGTACGAAGTTCAGTGGAAAGTTGTTGAAGAAATCAACGG 1776(SEQ ID NO: 5) 8K1B GGTCGATGTAAACGTAGTTGTTACCGTTGATTTCTTCAACAACTTT 1777(SEQ ID NO: 6) 8K2A AACAACTACGTTTACATCGACCCGACCCAGCTGCCGTACGAC 1779(SEQ ID NO: 7) 8K2B GTTACGCGGGAACTCCCATTTGTGGTCGTACGGCAGCTGGGTC 1781(SEQ ID NO: 8) 8K3A AAATGGGAGTTCCCGCGTAACCGTCTGTCTTTCGGTAAAACCC 1782(SEQ ID NO: 9) 8K3B ACCGAACGCACCCGCACCCAGGGTTTTACCGAAAGACAGAC 1783(SEQ ID NO: 10) 8K4A GGTGCGGGTGCGTTCGGTAAAGTTGTTGAAGCGACCGCGTACG 1784(SEQ ID NO: 11) 8K4B GCCGCGTCAGATTTGATCAGACCGTACGCGGTCGCTTCAAC 1785(SEQ ID NO: 12) 8K5A CTGATCAAATCTGACGCGGCGATGACCGTTGCGGTTAAAATGC 1786(SEQ ID NO: 13) 8K5B GTCAGGTGCGCAGACGGTTTCAGCATTTTAACCGCAACGGTCA 1787(SEQ ID NO: 14) 8K6A AAACCGTCTGCGCACCTGACCGAACGTGAAGCGCTGATGTCTG 1788(SEQ ID NO: 15) 8K6B CCAGGTAAGACAGAACTTTCAGTTCAGACATCAGCGCTTCACGT 1789(SEQ ID NO: 16) 8K7A CTGAAAGTTCTGTCTTACCTGGGTAACCACATGAACATCGTTAA 1791(SEQ ID NO: 17) 8K7B GGTGCACGCACCCAGCAGGTTAACGATGTTCATGTGGTTAC 1792(SEQ ID NO: 18) 8K8A CTGCTGGGTGCGTGCACCATCGGTGGTCCGACCCTGGTTATCA 1793(SEQ ID NO: 19) 8K8B GTCACCGTAGCAGCAGTATTCGGTGATAACCAGGGTCGGACCA 1794(SEQ ID NO: 20) 8K9A GAATACTGCTGCTACGGTGACCTGCTGAACTTCCTGCGTCGTA 1795(SEQ ID NO: 21) 8K9B AGAGCAGATGAAAGAGTCACGTTTACGACGCAGGAAGTTCAGC 1796(SEQ ID NO: 22) 8K10A CGTGACTCTTTCATCTGCTCTAAACAGGAAGACCACGCGGAAG 1797(SEQ ID NO: 23) 8K10B CAGCAGGTTTTTGTACAGCGCCGCTTCCGCGTGGTCTTCCTGT 1798(SEQ ID NO: 24) 8K11A GCGCTGTACAAAAACCTGCTGCACTCTAAAGAATCTTCTTGCTC 1799(SEQ ID NO: 25) 8K11B CCATGTATTCGTTGGTAGAGTCAGAGCAAGAAGATTCTTTAGAGT 1811(SEQ ID NO: 26) 8K11A GACTCTACCAACGAATACATGGACATGAAACCGGGTGTTTCTTA 1812(SEQ ID NO: 27) 8K11B TCCGCTTTGGTCGGAACAACGTAAGAAACACCCGGTTTCATGT 1813(SEQ ID NO: 28) 8K12A GTTGTTCCGACCAAAGCGGACAAACGTCGTTCTGTTCGTATCG 1814(SEQ ID NO: 29) 8K12B TAACGTCACGTTCGATGTAAGAACCGATACGAACAGAACGACGTTT1815 (SEQ ID NO: 30) 8K13A TCTTACATCGAACGTGACGTTACCCCGGCGATCATGGAAGACG1816 (SEQ ID NO: 31) 8K13B CCAGGTCCAGCGCCAGTTCGTCGTCTTCCATGATCGCCGG 1817(SEQ ID NO: 32) 8K14A GAACTGGCGCTGGACCTGGAAGACCTGCTGTCTTTCTCTTACC 1818(SEQ ID NO: 33) 8K14B GAACGCCATACCTTTCGCAACCTGGTAAGAGAAAGACAGCAGGT 1819(SEQ ID NO: 34) 8K15A GTTGCGAAAGGTATGGCGTTCCTGGCGTCTAAAAACTGCATCCA 1821(SEQ ID NO: 35) 8K15B CGCGCCGCCAGGTCACGGTGGATGCAGTTTTTAGACGCC 1822(SEQ ID NO: 36) 8K16A CGTGACCTGGCGGCGCGTAACATCCTGCTGACCCACGGTCG 1823(SEQ ID NO: 37) 8K16B ACCGAAGTCGCAGATTTTGGTGATACGACCGTGGGTCAGCAGG 1824(SEQ ID NO: 38) 8K17A ACCAAAATCTGCGACTTCGGTCTGGCGCGTGACATCAAAAACG 1825(SEQ ID NO: 39) 8K17B GTTACCTTTAACAACGTAGTTAGAGTCGTTTTTGATGTCACGCGCC1826 (SEQ ID NO: 40) 8K18A TCTAACTACGTTGTTAAAGGTAACGCGCGTCTGCCGGTTAAATG1827 (SEQ ID NO: 41) 8K18B GAAGATAGATTCCGGCGCCATCCATTTAACCGGCAGACGCGC1829 (SEQ ID NO: 42) 8K19A ATGGCGCCGGAATCTATCTTCAACTGCGTTTACACCTTCGAATC1831 (SEQ ID NO: 43) 8K19B GATACCGTAAGACCAAACGTCAGATTCGAAGGTGTAAACGCAG1832 (SEQ ID NO: 44) 8K20A GACGTTTGGTCTTACGGTATCTTCCTGTGGGAACTGTTCTCTC1833 (SEQ ID NO: 45) 8K20B CCTGTGGGAACTGTTCTCTCTGGGTTCTTCTCCGTACCCGG1834 (SEQ ID NO: 46) 8K21A GGTTCTTCTCCGTACCCGGGTATGCCGGTTGACTCTAAATTCTAT1835 (SEQ ID NO: 47) 8K21B CGGAAACCTTCTTTGATCATTTTGTAGAATTTAGAGTCAACCGGC1836 (SEQ ID NO: 48) 8K22A AAAATGATCAAAGAAGGTTTCCGTATGCTGTCTCCGGAACACG1837 (SEQ ID NO: 49) 8K22B ATGTCGTACATTTCCGCCGGCGCGTGTTCCGGAGACAGCATA1838 (SEQ ID NO: 50) 8K23A CCGGCGGAAATGTACGACATCATGAAAACCTGCTGGGACGCG1839 (SEQ ID NO: 51) 8K23B AAGGTCGGACGTTTCAGCGGGTCCGCGTCCCAGCAGGTTTTC1841 (SEQ ID NO: 52) 8K24A CCGCTGAAACGTCCGACCTTCAAACAGATCGTTCAGCTGATCG1842 (SEQ ID NO: 53) 8K24BTTGGTAGATTCAGAGATCTGTTTTTCGATCAGCTGAACGATCTGTT 1843 (SEQ ID NO: 54)8K25A AAACAGATCTCTGAATCTACCAACCACATCTACTCTAACCTGGC 1844 (SEQ ID NO: 55)8K25B TGACGGTTCGGAGAGCAGTTCGCCAGGTTAGAGTAGATGTGG 1845 (SEQ ID NO: 56)8K26A AACTGCTCTCCGAACCGTCAGAAACCGGTTGTTGACCACTCTG 1846 (SEQ ID NO: 57)8K26B GTAGAACCAACAGAGTTGATACGAACAGAGTGGTCAACAACCGGT 1847 (SEQ ID NO: 58)8K27A CGTATCAACTCTGTTGGTTCTACCGCGTCTTCTTCTCAGCCG 1848 (SEQ ID NO: 59)8K27B AACGTCGTCGTGAACCAGCAGCGGCTGAGAAGAAGACGCG 1849 (SEQ ID NO: 60) 8K-FGTTGTTTCATATGTACGAAGTTCAGTGGAAAG 1851 (SEQ ID NO: 61) 8K-RGTTGTTTGTCGACTAAACGTCGTCGTGAACCAGCAG 1852 (SEQ ID NO: 62) KIT COD-K948XGTTCTTGTCGACTAtttctgacggttcggagagc 3411 (SEQ ID NO: 63)P1332.N6 BI PTP KIT M552-K948-X COD(Nucleic Acid SEQ ID NO: 64) (Protein SEQ ID NO: 65)taatacgactcactataggggaattgtgagcggataacaattcccctctagaaataattttgtttaactttaagaaggagatataccatgggtcaccaccatcaccatcatatgtacgaa                            M  G  H  H  H  H  H  H  M  Y  Egttcagtggaaagttgttgaagaaatcaacggtaacaactacgtttacatcgacccgacc V  Q  W  K  V  V  E  E  I  N  G  N  N  Y  V  Y  I  D  P  Tcagctgccgtacgaccacaaatgggagttcccgcgtaaccgtctgtctttcggtaaaacc Q  L  P  Y  D  H  K  W  E  F  P  R  N  R  L  S  F  G  K  Tctgggtgcgggtgcgttcggtaaagttgttgaagcgaccgcgtacggtctgatcaaatct L  G  A  G  A  F  G  K  V  V  E  A  T  A  Y  G  L  I  K  Sgacgcggcgatgaccgttgcggttaaaatgctgaaaccgtctgcgcacctgaccgaacgt D  A  A  M  T  V  A  V  K  M  L  K  P  S  A  H  L  T  E  Rgaagcgctgatgtctgaactgaaagttctgtcttacctgggtaaccacatgaacatcgtt E  A  L  M  S  E  L  K  V  L  S  Y  L  G  N  H  M  N  I  Vaacctgctgggtgcgtgcaccatcggtggtccgaccctggttatcaccgaatactgctgc N  L  L  G  A  C  T  I  G  G  P  T  L  V  I  T  E  Y  C  Ctacggtgacctgctgaacttcctgcgtcgtaaacgtgactctttcatctgctctaaacag Y  G  D  L  L  N  F  L  R  R  K  R  D  S  F  I  C  S  K  Qgaagaccacgcggaagcggcgctgtacaaaaacctgctgcactctaaagaatcttcttgc E  D  H  A  E  A  A  L  Y  K  N  L  L  H  S  K  E  S  S  Ctctgactctaccaacgaatacatggacatgaaaccgggtgtttcttacgttgttccgacc S  D  S  T  N  E  Y  M  D  M  K  P  G  V  S  Y  V  V  P  Taaagcggacaaacgtcgttctgttcgtatcggttcttacatcgaacgtgacgttaccccg K  A  D  K  R  R  S  V  R  I  G  S  Y  I  E  R  D  V  T  Pgcgatcatggaagacgacgaactggcgctggacctggaagacctgctgtctttctcttac A  I  M  E  D  D  E  L  A  L  D  L  E  D  L  L  S  F  S  Ycaggttgcgaaaggtatggcgttcctggcgtctaaaaactgcatccaccgtgacctggcg Q  V  A  K  G  M  A  F  L  A  S  K  N  C  I  H  R  D  L  Agcgcgtaacatcctgctgacccacggtcgtatcaccaaaatctgcgacttcggtctggcg A  R  N  I  L  L  T  H  G  R  I  T  K  I  C  D  F  G  L  Acgtgacatcaaaaacgactctaactacgttgttaaaggtaacgcgcgtctgccggttaaa R  D  I  K  N  D  S  N  Y  V  V  K  G  N  A  R  L  P  V  Ktggatggcgccggaatctatcttcaactgcgtttacaccttcgaatctgacgtttggtct W  M  A  P  E  S  I  F  N  C  V  Y  T  F  E  S  D  V  W  Stacggtatcttcctgtgggaactgttctctctgggttcttctccgtacccgggtatgccg Y  G  I  F  L  W  E  L  F  S  L  G  S  S  P  Y  P  G  M  Pgttgactctaaattctacaaaatgatcaaagaaggtttccgtatgctgtctccggaacac V  D  S  K  F  Y  K  M  I  K  E  G  F  R  M  L  S  P  E  Hgcgccggcggaaatgtacgacatcatgaaaacctgctgggacgcggacccgctgaaacgt A  P  A  E  M  Y  D  I  M  K  T  C  W  D  A  D  P  L  K  Rccgaccttcaaacagatcgttcagctgatcgaaaaacagatctctgaatctaccaaccac P  T  F  K  Q  I  V  Q  L  I  E  K  Q  I  S  E  S  T  N  Hatctactctaacctggcgaactgctctccgaaccgtcagaaatagtcgactgaaaaagga I  Y  S  N  L  A  N  C  S  P  N  R  Q  K  - agagt

Additional Biochemical and Cell-Based Assays

In general, any protein kinase assay can be adapted for use with c-kit.For example, assays (e.g. biochemical and cell-based assays) asdescribed in Lipson et al., U.S. Patent Publ. 20040002534 (incorporatedherein by reference in its entirety) can be used in the presentinvention.

In Vivo Model System Testing

For in vivo testing, a suitable animal model system can be selected foruse. For example, for multiple sclerosis, the rodent experimentalallergic encephalomyelitis (EAE) is commently used. This system iswell-known, and is described, for example, in Steinman, 1996, Cell85:299-302 and Secor et al., 2000, J. Exp. Med. 5:813-821, which areincorporated herein by reference in their entireties.

Similarly, other model systems can be selected and used in the presentinvention.

Exemplary Fms Biochemical Assay

IC₅₀ values were determined with respect to inhibition of Fms kinaseactivity, where inhibition of phosphorylation of a peptide substrate ismeasured as a function of compound concentration. Compounds to betested, dissolved in DMSO (1 μL), were added to a white 384-well plate(Costar #3705). Working stocks of Fms kinase (Upstate Biotech, #14-551),biotin-(E4Y)₁₀ substrate (Upstate Biotech, Cat#12-440), and ATP (Sigma,Cat#A-3377) were prepared in 8 mM MOPS pH 7.4, 2 mM MgCl₂, 8 mM MnCl₂, 2mM DTT, and 0.01% Tween-20. All components were added to the 384-wellplate for a final concentration of 0.5 ng/well Fms, 30 nM biotin-(E4Y)₁₀(Upstate Biotechnology) and 10 μM ATP in a volume of 20 μL. Each samplewas at 5% DMSO. The plate was then incubated for 60 minutes at roomtemperature. Just before use, working stocks of donor and acceptor beadsfrom the AlphaScreen PY20 Detection Kit (PerkinElmer, Cat#676601M) wereprepared in 8 mM MOPS, pH 7.4, 100 mM EDTA, 0.3% BSA. To stop thereaction, the plate was uncovered in the dark and 5 μl of Donor Beadssolution (Streptavidin beads) was added to each well. The plate wasincubated at room temperature for 20 minutes. Five microliters ofAcceptor Beads solution (PY20 coated beads) were then added to eachwell. The final concentration of each bead was 20 μg/mL. The plates wereincubated at room temperature for 60 minutes. Fluorescence signal wasrecorded on the Fusion Alpha reader or AlphaQuest reader. Phosphorylatedsubstrate results in binding of the PY20 antibody and association of thedonor and acceptor beads such that signal correlates with kinaseactivity. The signal vs. compound concentration was used to determinethe IC₅₀.

Compounds were also tested using a similar assay with a 10-fold higherATP concentration. Compounds to be tested, dissolved in DMSO (1 μL),were added to a white 384-well plate (Costar #3705). Working stocks ofFms kinase (Upstate Biotech, #14-551), biotin-(E4Y)₁₀ substrate (UpstateBiotech, Cat#12-440), and ATP (Sigma, Cat#A-3377) were prepared in 25 mMHEPES pH 7.5, 0.5 mM MgCl₂, 2 mM MnCl₂,2 mM DTT, 0.01% BSA, and 0.01%Tween-20. All components were added to the 384-well plate for a finalconcentration of 0.5 ng/well Fms, 30 nM biotin-(E4Y)₁₀ (UpstateBiotechnology) and 100 μM ATP in a volume of 20 μL. Each sample was at5% DMSO. The plate was then incubated for minutes at room temperature.Just before use, working stocks of donor and acceptor beads from theAlphaScreen PY20 Detection Kit (PerkinElmer, Cat#676601M) were preparedin 25 mM HEPES pH 7.5, 100 mM EDTA, 0.01% BSA. To stop the reaction, theplate was uncovered in the dark and 5 μl of Donor Beads solution(Streptavidin beads) was added to each well. The plate was incubated atroom temperature for 20 minutes. Five microliters of Acceptor Beadssolution (PY20 coated beads) were then added to each well. The finalconcentration of each bead was 10 μg/mL. The plates were incubated atroom temperature for 60 minutes. Fluorescence signal was recorded on theAlphaQuest or Envision reader. Phosphorylated substrate results inbinding of the PY20 antibody and association of the donor and acceptorbeads such that signal correlates with kinase activity. The signal vs.compound concentration was used to determine the IC₅₀.

Compounds were assayed using a similar assay to that described above,using in a final reaction volume of 25 μl: Fms (h) (5-10 mU) in 8 mMMOPS pH 7.0, 0.2 mM EDTA, 250 mM KKKSPGEYVNIEFG (SEQ ID NO:66), 10 mMMgAcetate and γ- ³³P-ATP (approximately 500 cpm/μmol), with appropriateconcentrations of compound. Samples were incubated for 40 minutes atroom temperature and stopped by addition of 5 μl of 3% phosphoric acid.10 μl of each sample is spotted onto a P30 filtermat and washed 3× with75 mM phosphoric acid, once with methanol, dried and measured onscintillation counter (Upstate USA, Charlottesville, Va.).

Compounds P-0001, P-0002, P-0003, P-0004, P-0005, P-0006, P-0007,P-0008, P-0009, P-0010, P-0011, P-0013, P-0014, P-0015, P-0016, P-0028,P-0032, P-0033, P-0038, P-0053, P-0054, P-0055, P-0056, P-0057, P-0058,P-0059, P-0060, P-0061, P-0062, P-0063, P-0064, P-0065, P-0066, P-0069,P-0072, P-0073, P-0074, P-0075, P-0076, P-0078, P-0081, P-0082, P-0092,P-0093, P-0094, P-0095, P-0096, P-0097, P-0098, P-0099, P-0100, P-0101,P-0102, P-0103, P-0104, P-0105, P-0106, P-0107, P-0108, P-0109, P-0110,P-0111, P-0112, P-0113, P-0114, P-0115, P-0116, P-0117, P-0118, P-0119,P-0120, P-0121, P-0122, P-0123, P-0125, P-0126, P-0127, P-0128, P-0129,P-0130, P-0131, P-0132, P-0134, P-0135, P-0136, P-0137, P-0140, P-0141,P-0142, P-0143, P-0144, P-0145, P-0146, P-0147, P-0148, P-0149, P-0150,P-0151, P-0152, P-0153, P-0154, P-0156, P-0157, P-0158, P-0159, P-0160,P-0161, P-0163, P-0164, P-0165, P-0167, P-0168, P-0169, P-0170, P-0171,P-0172, P-0173, P-0174, P-0175, P-0176, P-0179, P-0180, P-0181, P-0182,P-0183, P-0185, P-0186, P-0187, P-0188, P-0189, P-0190, P-0191, P-0192,P-0193, P-0194, P-0195, P-0196, P-0197, P-0198, P-0199, P-0200, P-0201,P-0202, P-0203, P-0204, P-0205, P-0206, P-0207, P-0208, P-0209, P-0210,P-0211, P-0212, P-0213, P-0214, P-0215, P-0216, P-0217, P-0218, P-0219,P-0220, P-0221, P-0222, P-0223, P-0224, P-0225, P-0226, P-0227, P-0228,P-0229, P-0230, P-0231, P-0232, P-0233, P-0234, P-0235, P-0236, P-0237,P-0238, P-0239, P-0240, P-0241, P-0242, P-0243, P-0244, P-0245, P-0246,P-0247, P-0248, P-0249, P-0250, P-0251, P-0252, P-0253, P-0254, P-0255,P-0256, P-0257, P-0258, P-0259, P-0260, P-0261, P-0262, P-0263, P-0264,P-0265, P-0266, P-0267, P-0268, P-0269, P-0270, P-0271, P-0272, P-0273,P-0274, P-0275, P-0276, P-0277, P-0278, P-0279, P-0280, P-0281, P-0282,P-0283, P-0284, P-0285, P-0286, P-0287, P-0288, P-0289, P-0290, P-0291,P-0292, P-0293, P-0294, P-0295, P-0296, P-0297, P-0298, P-0299, P-0300,P-0301, P-0302, P-0303, P-0304, P-0305, P-0306, P-0307, P-0308, P-0309,P-0310, P-0311, P-0312, P-0313, P-0314, P-0315, P-0316, P-0317, P-0318,P-0319, P-0320, P-0321, P-0322, P-0323, P-0324, P-0325, P-0326, P-0327,P-0328, P-0329, P-0330, P-0331, P-0332, P-0333, P-0334, P-0335, P-0336,P-0337, P-0338, P-0339, P-0340, P-0341, P-0342, P-0343, P-0344, P-0345,P-0346, P-0347, P-0348, P-0349, P-0350, P-0351, P-0352, P-0353, P-0354,P-0355, P-0356, P-0357, P-0358, P-0359, P-0360, P-0361, P-0362, P-0363,P-0364, P-0365, P-0366, P-0367, P-0368, P-0369, P-0370, P-0371, P-0372,P-0373, P-0374, P-0375, P-0376, P-0377, P-0378, P-0379, P-0380, P-0381,P-0382, P-0383, P-0384, P-0385, P-0386, P-0387, P-0390, P-0391, P-0392,P-0393, P-0394, P-0395, P-0396, P-0402, P-0403, P-0404, P-0405, P-0406,P-0407, P-0408, P-0409, and P-0412 had IC₅₀ of less than 1 μM in atleast one of the Fms assays described above in Examples 40 or 41.

Exemplary TrkA Biochemical Assay

Compounds were similarly assayed to determine IC₅₀ values with respectto inhibition of TrkA kinase activity, where inhibition ofphosphorylation of a peptide substrate was measured as a function ofcompound concentration. Compounds tested were dissolved in DMSO (1 μL)and added to a white 384-well plate (Costar #3705). Working stocks ofTrkA kinase (Upstate Biotech, #14-571), biotin-(E4Y)₁₀ substrate(Upstate Biotech, Cat#12-440), and ATP (Sigma, Cat#A-3377) were preparedin 25 mM Hepes pH 7.5, 10 mM MnCl₂, 1 mM DTT, and 0.01% Tween-20. Allcomponents were added to the 384-well plate for a final concentration of1 ng/well TrkA, 30 nM biotin-(E4Y)₁₀ (Upstate Biotechnology) and 100 μMATP in a volume of 20 μL. Each sample was at 5% DMSO. The plate was thenincubated for minutes at room temperature. Just before use, workingstocks of donor and acceptor beads from the AlphaScreen PY20 DetectionKit (PerkinElmer, Cat#676601M) were prepared in 25 mM Hepes pH 7.5, 100mM EDTA, 0.3% BSA. To stop the reaction, the plate was uncovered in thedark and 5 μl of Donor Beads solution (Streptavidin beads) was added toeach well. The plate was incubated at room temperature for 20 minutes.Five microliters of Acceptor Beads solution (PY20 coated beads) werethen added to each well. The final concentration of each bead was 10μg/mL. The plates were incubated at room temperature for 60 minutes.Fluorescence signal was recorded on the AlphaQuest or Envision reader.Phosphorylated substrate results in binding of the PY20 antibody andassociation of the donor and acceptor beads such that signal correlateswith kinase activity. The signal vs. compound concentration was used todetermine the IC₅₀. Compounds P-0157, P-0171, P-0179, P-0180, P-0303,and P-0412 had IC₅₀ of less than 1 μM in this TrkA assay.

Exemplary HGK Biochemical Assay

The MAP4K₄ (or kinase domain thereof) is an active kinase inAlphaScreen. IC₅₀ values are determined with respect to inhibition ofMAP4K₄ kinase activity, where inhibition of phosphorylation of a peptidesubstrate is measured as a function of compound concentration. Compoundsto be tested were dissolved in DMSO to a concentration of 20 mM. Thesewere diluted 30 μl into 120 μl of DMSO (4 mM) and 1 μl was added to anassay plate. These were then serially diluted 1:3 (50 μl to 100 μl DMSO)for a total of 8 points. Plates were prepared such that each kinasereaction is 20 μl in 1× kinase buffer (20 mM Tris, pH 7.4, 10 mM MgCl₂,1 mM DTT, 0.01% Tween-20), 5% DMSO and 10 μM ATP. Substrate was 10 nMbiotin-ERM (T567/T564/T558, Cell Signaling, Inc., cat#1344). MAP4K₄kinase was at 0.5 ng per sample. After incubation of the kinase reactionfor 40 min at room temperature, 5 μl of donor beads and protein Aacceptor beads (Perkin Elmer Life Science, cat#67606017) at finalconcentration 1 μg/ml in stop buffer (20 mM Tris, pH 7.4, 200 mM Nacl,100 mM EDTA, 0.03% BSA) was added, along with Phospho-ERM Antibody(T567/T564/T558, Cell Signaling, Inc., cat#3141) at 1:1000 dilution. Thesamples were incubated for 2 hours at room temperature and the signalper well was read on AlphaQuest reader. Phosphorylated substrate resultsin binding of the antibody which binds to protein A acceptor bead andassociation of the donor and acceptor beads is such that the signalcorrelates with kinase activity. The signal vs. compound concentrationwas used to determine the IC₅₀. Compounds P-0156, P-0177, P-0179,P-0195, P-0201, P-0203, P-0206, P-0207, P-0231, P-0240, P-0241, P-0255,P-0324, P-0341, and P-0403 had IC₅₀ of less than 1 μM in this HGK assay.

Example 42 Site-Directed Mutagenesis of c-Kit, c-Fms and Other Kinases

Mutagenesis of c-kit and other kinases (as well as other sequences ofinterest) can be carried out according to the following procedure asdescribed in Molecular Biology: Current Innovations and Future Trends.Eds. A. M. Griffin and H. G. Griffin. (1995) ISBN 1-898486-01-8, HorizonScientific Press, PO Box 1, Wymondham, Norfolk, U.K., among others.

In vitro site-directed mutagenesis is an invaluable technique forstudying protein structure-function relationships, gene expression andvector modification. Several methods have appeared in the literature,but many of these methods require single-stranded DNA as the template.The reason for this, historically, has been the need for separating thecomplementary strands to prevent reannealing. Use of PCR insite-directed mutagenesis accomplishes strand separation by using adenaturing step to separate the complementing strands and allowingefficient polymerization of the PCR primers. PCR site-directed methodsthus allow site-specific mutations to be incorporated in virtually anydouble-stranded plasmid; eliminating the need for M13-based vectors orsingle-stranded rescue.

It is often desirable to reduce the number of cycles during PCR whenperforming PCR-based site-directed mutagenesis to prevent clonalexpansion of any (undesired) second-site mutations. Limited cyclingwhich would result in reduced product yield, is offset by increasing thestarting template concentration. A selection is used to reduce thenumber of parental molecules coming through the reaction. Also, in orderto use a single PCR primer set, it is desirable to optimize the long PCRmethod. Further, because of the extendase activity of some thermostablepolymerases it is often necessary to incorporate an end-polishing stepinto the procedure prior to end-to-end ligation of the PCR-generatedproduct containing the incorporated mutations in one or both PCRprimers.

The following protocol provides a facile method for site-directedmutagenesis and accomplishes the above desired features by theincorporation of the following steps: (i) increasing templateconcentration approximately 1000-fold over conventional PCR conditions;(ii) reducing the number of cycles from 25-30 to 5-10; (iii) adding therestriction endonuclease DpnI (recognition target sequence: 5-Gm6ATC-3,where the A residue is methylated) to select against parental DNA (note:DNA isolated from almost all common strains of E. coli is Dam-methylatedat the sequence 5-GATC-3); (iv) using Taq Extender in the PCR mix forincreased reliability for PCR to 10 kb; (v) using Pfu DNA polymerase topolish the ends of the PCR product, and (vi) efficient intramolecularligation in the presence of T4 DNA ligase.

Plasmid template DNA (approximately 0.5 pmole) is added to a PCRcocktail containing, in 25 ul of 1× mutagenesis buffer: (20 mM Tris HCl,pH 7.5; 8 mM MgCl₂; 40 ug/ml BSA); 12-20 pmole of each primer (one ofwhich must contain a 5-prime phosphate), 250 uM each dNTP, 2.5 U Taq DNApolymerase, 2.5 U of Taq Extender (Stratagene).

The PCR cycling parameters are 1 cycle of: 4 min at 94° C., 2 min at 50C and 2 min at 72° C.; followed by 5-10 cycles of 1 min at 94° C., 2 minat 54 C and 1 min at 72° C. (step 1).

The parental template DNA and the linear, mutagenesis-primerincorporating newly synthesized DNA are treated with DpnI (10 U) and PfuDNA polymerase (2.5 U). This results in the DpnI digestion of the invivo methylated parental template and hybrid DNA and the removal, by PfuDNA polymerase, of the Taq DNA polymerase-extended base(s) on the linearPCR product.

The reaction is incubated at 37° C. for 30 min and then transferred to72° C. for an additional 30 min (step 2).

Mutagenesis buffer (1×, 115 ul, containing 0.5 mM ATP) is added to theDpnI-digested, Pfu DNA polymerase-polished PCR products.

The solution is mixed and 10 ul is removed to a new microfuge tube andT4 DNA ligase (2-4 U) added.

The ligation is incubated for greater than 60 min at 37° C. (step 3).

The treated solution is transformed into competent E. coli (step 4).

In addition to the PCR-based site-directed mutagenesis described above,other methods are available. Examples include those described in Kunkel(1985) Proc. Natl. Acad. Sci. 82:488-492; Eckstein et al. (1985) Nucl.Acids Res. 13:8764-8785; and using the GeneEditor™ Site-DirectedMutagenesis System from Promega.

Example 43 Synthesis of3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylicacid benzylamide P-0084

3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylicacid benzylamide P-0084 was synthesized in 6 steps fromdimethyl-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine 2 as shown inScheme 158.

Step 1: Preparation of3-Dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester (511)

To dimethyl-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine (2, 2.50 g, 14.3mmol, prepared as described in Example 2, Scheme 4, Step 1) intetrahydrofuran (200.0 mL) was added sodium hydride (0.685 g, 60% inmineral oil, 17.1 mmol). After 10 minutes, di-tert-butyldicarbonate(3.74 g, 17.1 mmol) was added to the reaction. The reaction was stirredat room temperature overnight. The reaction was poured into water andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 30% ethyl acetate inhexane to give as a white solid (511, 3.80 g, 96.7%).

Step 2: Preparation of3-Chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester(512)

To 3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester (511, 2.60 g, 9.44 mmol) in toluene (50.00 mL) wasadded isopropyl chloroformate (11.3 mL, 1.0 M in toluene) under anatmosphere of nitrogen. The reaction was stirred at room temperature for3 hours. The reaction was poured into water and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 20% ethyl acetate in hexane to give awhite solid (512, 2.0 g, 79.4%).

Step 3—Preparation of3-(2-Acetyl-3-oxo-butyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester (513)

To acetylacetone (0.563 g, 5.62 mmol) in dimethyl sulfoxide (29.0 mL)was added sodium hydride (0.225 g, 60% in mineral oil, 5.62 mmol). After20 minutes, 3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester (512, 1.00 g, 3.75 mmol) was added to the reaction. Thereaction was stirred at room temperature for 2 hours. The reaction waspoured into water and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 40% ethyl acetate in hexane to give a colorless oil (513, 0.59 g,48.0%). MS (ESI) [M+H⁺]⁺=331.4.

Step 4—Preparation of3-(3,5-Dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (514)

To 3-(2-acetyl-3-oxo-butyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester (513, 1.20 g, 3.63 mmol) in methanol (15.0 mL), cooledto −20° C. under an atmosphere of nitrogen, was added hydrazine (0.128g, 4.00 mmol) in dichloromethane (6.0 mL). The reaction was stirred for2 hours. The reaction was concentrated to remove the solvents, and theresidue was poured into water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 60% ethyl acetate in hexane to give a whitesolid (514, 1.0 g, 84.4%). MS (ESI) [M+H⁺]⁺=327.4.

Step 5—Preparation of3-(1-Benzylcarbamoyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (515)

To3-(3,5-dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (514, 60.0 mg, 0.18 mmol) in dichloromethane (6.0mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.033 mL, 0.220 mmol)and benzyl isocyanate (29.4 mg, 0.220 mmol) under an atmosphere ofnitrogen. The reaction was stirred at room temperature for 2 hours. Thereaction was concentrated and purified by silica gel columnchromatography eluting with 30% ethyl acetate in hexane to give crudecompound (515, approx. 50 mg) that was used in the next step directly.MS (ESI) [M+H⁺]⁺=460.5.

Step6-3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylicacid benzylamide (P-0084)

To3-(1-benzylcarbamoyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (515, 50.0 mg, 0.11 mmol) in dichloromethane (6.0mL) was added trifluoroacetic acid (0.20 mL, 2.6 mmol) under anatmosphere of nitrogen. The reaction was stirred at room temperature for20 minutes. The reaction was poured into aqueous potassium carbonate andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 30% ethyl acetate inhexane to give a white solid (P-0084, 11.0 mg, 28.1%). MS (ESI)[M+H]⁺=360.5.

3-(3,5-Dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine P-0124

was prepared from3-(3,5-Dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (514, 15.0 mg, 0.046 mmol) by dissolving indichloromethane (10.0 mL) to which trifluoroacetic acid (0.10 mL, 1.3mmol) was added. The reaction was stirred at room temperature for 1hour, then poured into aqueous potassium carbonate and extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated and washed with ethylacetate in hexane to give an off-white solid (P-0124, 7.5 mg, 72.0%). MS(ESI) [M+H⁺]⁺=227.3.

Additional compounds were prepared following the protocol of Scheme 158,replacing benzyl isocyanate with an appropriate electrophile in Step 5.The following compounds were made following this procedure:

-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid phenylamide (P-0085),-   [3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazol-1-yl]-phenyl-methanone    (P-0086),-   1-[3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazol-1-yl]-3-phenyl-propan-1-one    (P-0087),-   3-(3,5-Dimethyl-1-phenylmethanesulfonyl-1H-pyrazol-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine    (P-0088),-   3-[1-(Butane-1-sulfonyl)-3,5-dimethyl-1H-pyrazol-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine    (P-0089),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid butylamide (P-0090), and-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid phenethyl-amide (P-0091).

The electrophile used in place of benzyl isocyanate in Step 5 isindicated in Column 2 of the following table, with the compoundstructure given in Column 3. Column 1 provides the compound number andColumn 4 the experimental mass spectrometry result.

MS(ESI) [M + H⁺]⁺ Electrophile Compound observed P-0085

346.4 P-0086

331.2 P-0087

359.2 P-0088

381.2 P-0089

347.2 P-0090

326.2 P-0091

Additional compounds were prepared following the protocol of Scheme 158,replacing dimethyl-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine 2 with(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-dimethyl-amine (preparedas described in Example 107, Scheme 164, isolated after step 1) in Step1 and replacing benzyl isocyanate with an appropriate electrophile inStep 5. The following compounds were made following this procedure:

-   4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic    acid [2-(4-fluoro-phenyl)-ethyl]-amide (P-0157),-   4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic    acid 4-fluoro-benzylamide (P-0158),-   4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic    acid 4-chloro-benzylamide (P-0159), and-   4-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-1-carboxylic    acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide (P-0160).

The electrophile used in place of benzyl isocyanate in Step 5 isindicated in Column 2 of the following table, with the compoundstructure given in Column 3. Column 1 provides the compound number andColumn 4 the experimental mass spectrometry result.

MS(ESI) [M + H⁺]⁺ Electrophile Compound observed P-0157

426.2 P-0158

412.2 P-0159

428.2 P-0160

462.2

Example 44 Synthesis of[4-chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amineP-0168

[4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amineP-0168 was synthesized in 5 steps as shown in Scheme 159.

Step 1—Preparation of4-chloro-2-[(pyridin-4-ylmethyl)-amino]-thiazole-5-carbaldehyde (517)

To a solution of 4-(aminomethyl)pyridine (516, 1.16 mL, 11.5 mmol) andN,N-diisopropylethylamine (3.8 mL, 22 mmol) in tetrahydrofuran (50 mL)was added 2,4-dichloro-thiazole-5-carbaldehyde (93, 2.0 g, 11.0 mmol) intetrahydrofuran (5 mL) at room temperature. The reaction mixture wasstirred at room temperature overnight. The reaction mixture was pouredinto ice water, extracted with ethyl acetate, washed with brine, anddried over sodium sulfate. The crude compound4-chloro-2-[(pyridin-4-ylmethyl)-amino]-thiazole-5-carbaldehyde (517)was used for the next step without purification.

Step 2—Preparation of(4-chloro-5-formyl-thiazol-2-yl)-pyridin-4-ylmethyl-carbamic acidtert-butyl ester (518)

A mixture of4-chloro-2-[(pyridin-4-ylmethyl)-amino]-thiazole-5-carbaldehyde (517,3.28 g, 11.0 mmol), di-tert-butyldicarbonate (4.0 g, 18 mol) andtriethylamine (10 mL, 74 mmol) in dichloromethane (120 mL) was stirredat room temperature for 6 hours. The reaction mixture was poured intoice water, extracted with ethyl acetate, washed with brine, and driedover sodium sulfate. After removal of solvent, the residue was purifiedby silica gel column chromatography eluting with ethyl acetate inhexanes to provide the desired compound as a yellow solid (518, 564 mg,15%). MS (ESI) [M+H]⁺=354.1.

Step 3—Preparation of{4-chloro-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-thiazol-2-yl}-pyridin-4-ylmethyl-carbamicacid tert-butyl ester (519)

To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(96, 0.44 g, 1.1 mmol) in tetrahydrofuran (20 mL) at −20° C.,isopropylmagnesium chloride (2 M in tetrahydrofuran, 0.6 mL, 1.2 mmol)was added dropwise. The reaction mixture was allowed to warm to 0° C. in10 minutes. The reaction mixture was then cooled to −40° C. A solutionof (4-chloro-5-formyl-thiazol-2-yl)-pyridin-4-ylmethyl-carbamic acidtert-butyl ester (518, 0.26 g, 0.73 mmol) in tetrahydrofuran (4 mL) wasadded to the reaction mixture. The reaction mixture was allowed to warmto −10° C. over 30 minutes. The reaction mixture was poured into icewater, extracted with ethyl acetate, washed with brine, and dried oversodium sulfate. After removal of solvent, the residue was purified bysilica gel column chromatography eluting with ethyl acetate in hexanesto provide the desired compound as a yellow solid (519, 397 mg, 86%). MS(ESI) [M+H⁺]⁺=628.3.

Step 4—Preparation of[4-chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-carbamicacid tert-butyl ester (520)

A mixture of{4-chloro-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-thiazol-2-yl}-pyridin-4-ylmethyl-carbamicacid tert-butyl ester (519, 0.397 g, 0.57 mmol), triethylsilane (1.0 mL,6.3 mmol), and trifluoroacetic acid (0.5 mL, 6 mmol) in acetonitrile (10mL) was stirred at 40° C. for 2 hours. The reaction mixture was pouredinto ice water, extracted with ethyl acetate, washed with sodiumbicarbonate, washed with brine, and dried over sodium sulfate. Afterremoval of solvent, the residue was purified by silica gel columnchromatography eluting with methanol in dichloromethane to provide thedesired compound as a yellow solid (520, 126 mg, 49%). MS (ESI)[M+H]⁺=456.2.

Step 5—Preparation of[4-chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amine(P-0168)

To a solution of[4-chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-carbamicacid tert-butyl ester (520, 126 mg, 0.000276 mol) in dichloromethane (2mL) was added hydrogen chloride (4 M in 1,4-dioxane, 2 mL). The reactionmixture was stirred at room temperature overnight. The reaction mixturewas poured into cold sodium bicarbonate solution, extracted with ethylacetate, washed with brine and dried over magnesium sulfate. Afterremoval of solvents, the residue was washed with ethyl acetate toprovide the desired compound as a light yellow solid (P-0168, 68.4 mg,70%). MS (ESI) [M+H]⁺=356.2.

Additional compounds were prepared following the protocol of Scheme 159,replacing 4-(aminomethyl)pyridine 516 with an appropriate amine. Thefollowing compounds were made following this procedure:

-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl-amine    (P-0164),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-2-ylmethyl-amine    (P-0167),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2-ylmethyl)-amine    (P-0171),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0173),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-((1,5-dimethyl-1H-pyrazol-3-ylmethyl)-amine    (P-0172),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-amine    (P-0175), and-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine    (P-0156).

The following table indicates the amine (Column 2) used in Scheme 159 toprovide the compounds (Column 3). Column 1 provides the compound numberand Column 4 the observed mass.

MS(ESI) Compound [M + H⁺]⁺ number Amine Compound observed P-0164

356.1 P-0167

356.1 P-0171

370.2 P-0173

424.2 P-0172

373.2 P-0175

373.2 P-0156

373.1

Example 45 Synthesis of[4-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amineP-0162 and(4-fluoro-benzyl)-[4-methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amineP-0162

[4-Ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amineP-0162 was synthesized in 1 step from[4-chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amineP-0156 as shown in Scheme 160.

Step 1—Preparation of[4-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine(P-0162)

Into a round bottom flask, under an atmosphere of nitrogen,[1,1′-bis(diphenyl phosphino) ferrocene]dichloro palladium (II), complexwith dichloromethane (1:1), was placed with toluene (15 mL, 140 mmol).[4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine(P-0156,145 mg, 0.4 mmol) was added in 5 ml of toluene at roomtemperature. The mixture was stirred for 10 minutes. To the stirringreaction, a solution of 3.13 Methyl magnesium bromide in ether (1.86 mL)was added dropwise at room temperature. The opaque solution was heatedto 60° C. Tetrahydrofuran (10 mL) was added to the warm solution. Themixture was heated to reflux for an additional two hours. After coolingto 0° C., the reaction was quenched with a solution of citric acid at pH4-5 in ice-water and stirred to room temperature. The mixture wasdiluted with ethyl acetate and washed with saturated sodium bicarbonateand brine. The organic layer was dried over anhydrous sodium sulfate andthe solvent was removed under reduced pressure. Purification with flashchromatography, eluting with a gradient of ethyl acetate:hexanes(20:100), gave a yellow solid that was further washed with ethyl acetateto give P-0162 (15 mg, 10%) as an off-white solid. MS (ESI)[M+H⁺]⁺=367.2.

(4-Fluoro-benzyl)-[4-methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amineP-0163

was prepared using the protocol of Scheme 160, substituting the 3.13Methyl magnesium bromide in ether solution with 1.4 M of methylmagnesiumbromide in tetrahydrofuran. MS (ESI) [M+H]=353.2.

Example 46 Synthesis of(4-Chloro-benzyl)-[6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridazin-3-yl]-amineP-0092

(4-Chloro-benzyl)-[6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridazin-3-yl]-amineP-0092 was synthesized in 3 steps as shown in Scheme 161.

Step 1—Synthesis of (6-bromo-pyridazin-3-yl)-(4-chloro-benzyl)-amine(522)

To 6-bromo-pyridazin-3-ylamine (521, 0.85 g, 0.0049 mol) in acetonitrile(30.0 mL) were added 4-chlorobenzaldehyde (40, 0.82 g, 0.0058 mol),triethylsilane (4.0 mL, 0.025 mol) and trifluoroacetic acid (2.0 mL,0.026 mol). The reaction was heated to reflux for 4 hours, then pouredinto water, and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated and washed with ethyl acetate to give awhite solid (522, 1.0 g). MS (ESI) [M+H⁺]⁺=298.3, 300.2.

Step 2—Preparation of3-[6-(4-chloro-benzylamino)-pyridazin-3-ylmethyl]-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (523)

To (6-bromo-pyridazin-3-yl)-(4-chloro-benzyl)-amine (522, 0.560 g, 1.88mmol) in tetrahydrofuran (45.0 mL), under an atmosphere of nitrogen at−78° C., was added n-butyllithium (2.50 M in hexane, 0.760 mL) slowly.After 10 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (0.201 g,0.94 mmol) in tetrahydrofuran (5.0 mL) was added to the reaction. Thereaction mixture was allowed to stir at room temperature for 3 hours.The reaction was cooled to −78° C., followed by addition of 1.70 M oftert-butyllithium in hexane (1.20 mL) slowly. The reaction was stirredfor 20 minutes, followed by addition of a solution of CuCN.2LiCl (0.6 Min tetrahydrofuran, 3.00 mL) and3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester(512, 0.47 g, 1.8 mol) in tetrahydrofuran (10.0 mL). After 30 minutes,the reaction was allowed to warm to room temperature for 10 minutes. Thereaction was poured into water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was treated with trifluoroacetic acid (1.0 mL) dissolved indichloromethane (10.0 mL) for 10 minutes. The reaction was concentrated,poured into aqueous potassium carbonate and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated and purified with silica gelcolumn chromatography eluting with 60% ethyl acetate in hexane to givethe desired compound (523, 0.10 g, 23.8%). MS (ESI) [M+H⁺]⁺=450.1.

Step 3—Preparation of(4-chloro-benzyl)-[6-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridazin-3-yl]-amine(P-0092)

To3-[6-(4-chloro-benzylamino)-pyridazin-3-ylmethyl]-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (523, 50.0 mg, 0.111 mmol) in dichloromethane(10.0 mL) was added trifluoroacetic acid (0.30 mL, 0.0039 mol). Thereaction was stirred at room temperature overnight. The reaction wasconcentrated, poured into aqueous potassium carbonate and extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated and washed with ethylacetate and hexane to give an off-white solid (P-0092, 7.3 mg, 19.0%).MS (ESI) [M+H⁺]⁺=350.1.

Example 47 Synthesis of[1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amineP-0165

[1-Ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amineP-0165 was synthesized in 7 steps as shown in Scheme 162.

Step 1—Preparation of 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester(525)

To 5-nitro-2H-pyrazole-3-carboxylic acid (524, 10.0 g, 0.0637 mol) inmethanol (100.0 mL) was added concentrated sulfuric acid (1.00 mL,0.0180 mol). The reaction was stirred at room temperature overnight. Thereaction was poured into aqueous potassium carbonate and extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 20% ethyl acetate in hexane to give awhite solid (525, 1.5 g, 13.8%).

Step 2—Preparation of 2-ethyl-5-nitro-2H-pyrazole-3-carboxylic acidmethyl ester (526)

To 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (525, 2.50 g,0.0146 mol) in N,N-dimethylformamide (62.5 mL) were added iodoethane(1.2 mL, 0.016 mol) and potassium carbonate (4.17 g, 0.0301 mol) underan atmosphere of nitrogen. The reaction was stirred at room temperatureovernight. The reaction was poured into water and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 20% to 100% ethyl acetate in hexaneto give a white solid (526, 1.3 g, 44.7%).

Step 3—Preparation of 5-amino-2-ethyl-2H-pyrazole-3-carboxylic acidmethyl ester (527)

To 2-ethyl-5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (526, 1.30g, 6.53 mmol) in methanol (60.0 mL) was added 20% Pd(OH)₂/C (0.1 g). Thereaction was stirred under an atmosphere of hydrogen overnight. Thereaction was filtered and concentrated to give a light yellow solid(527, 1.0 g, 90.6%).

Step 4—Preparation of2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carboxylic acid methylester (529)

To 5-amino-2-ethyl-2H-pyrazole-3-carboxylic acid methyl ester (527, 1.00g, 5.91 mmol) in acetonitrile (27.5 mL) were added 4-fluorobenzaldehyde(528, 0.660 mL, 6.26 mmol), triethylsilane (4.77 mL, 0.0298 mol) andtrifluoroacetic acid (2.38 mL, 0.0310 mol). The reaction was stirred at80° C. for 4 hours, then concentrated, poured into aqueous potassiumcarbonate, and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% to 100% ethyl acetate in hexane to give a white solid (529,1.00 g, 61%).

Step 5—Preparation of2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530)

To 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carboxylic acid methylester (529, 1.00 g, 3.61 mol) in tetrahydrofuran (70.0 mL) under anatmosphere of nitrogen at room temperature, lithium tetrahydroaluminate(1.00 M of in tetrahydrofuran, 10.00 mL) was slowly added. The reactionwas stirred at room temperature overnight, followed by slowly addingsodium sulfate decahydrate (15.0 g). After 2 hours, the reaction wasfiltered, concentrated and purified with silica gel columnchromatography eluting with 20% to 100% ethyl acetate in hexane to givea yellow oil (530, 0.16 g, 18%). MS (ESI) [M+H⁺]⁺=248.2.

Step 6—Preparation of1-ethyl-5-[methoxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-1H-pyrazol-3-yl-(4-fluoro-benzyl)-amine(531)

To 1H-Pyrrolo[2,3-b]pyridine (1, 54.0 mg, 0.46 mmol) in methanol (15.0mL) were added2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 110.0mg, 0.44 mmol) and potassium hydroxide (0.60 g, 0.011 mol) under anatmosphere of nitrogen. The reaction was stirred at room temperatureovernight, then poured into water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 40% ethyl acetate in hexane to give a whitesolid (531, 0.12 g, 71.1%). MS (ESI) [M−H⁺]⁻=378.2.

Step 7—Preparation of[1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine(P-0165)

To1-ethyl-5-[methoxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-1H-pyrazol-3-yl-(4-fluoro-benzyl)-amine(531, 0.12 g, 0.32 mmol) in acetonitrile (10.0 mL, 0.191 mol) were addedtriethylsilane (0.60 mL, 0.0038 mol) and trifluoroacetic acid (0.30 mL,0.0039 mol). The reaction was stirred at 80° C. for 2 hours. Thereaction was poured into aqueous potassium carbonate and extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated and washed with ethylacetate and hexane to give crude compound. ¹H NMR indicated that thereaction was incomplete. The crude compound was dissolved indichloromethane (15.0 mL), trifluoroacetic acid (0.30 mL) andtriethylsilane (0.60 mL). The reaction was stirred at 43° C. for 72hours. The reaction was concentrated, poured into aqueous potassiumcarbonate and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and washed with ethyl acetate and hexane to give anoff-white solid (P-0165, 18.7 mg, 17%). MS (ESI) [M+H⁺]⁺=350.3.

(4-Fluoro-benzyl)-[1-methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-amineP-0169

was prepared using the protocol of Scheme 162, substituting iodoethanewith iodomethane in Step 2. MS (ESI) [M+H⁺]⁺=336.3.

[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amineP-0170

was prepared using the protocol of Scheme 162, substituting iodoethanewith iodomethane in step 2 and 1H-pyrrolo[2,3-b]pyridine 1 with5-chloro-1H-pyrrolo[2,3-b]pyridine in step 6.

MS (ESI) [M+H⁺]⁺=370.3

(4-Fluoro-benzyl)-{1-methyl-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-1H-pyrazol-3-yl}-amineP-0180

was prepared using the protocol of Scheme 162, substituting iodoethanewith iodomethane in step 2 and 1H-Pyrrolo[2,3-b]pyridine 1 with5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (prepared asdescribed in Example 115, Scheme 172) in step 6. MS (ESI) [M+H⁺]⁺=416.2.

3-[5-(4-Fluoro-benzylamino)-2-methyl-2H-pyrazol-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrileP-0191

was prepared using the protocol of Scheme 162, substituting1H-Pyrrolo[2,3-b]pyridine 1 with1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile in Step 6. MS (ESI)[M+H⁺]⁺=361.5.

Example 48 Synthesis of[4-chloro-1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-amineP-0166

[4-chloro-1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-amineP-0166 was synthesized in 1 step as shown in Scheme 163.

Step 1—Preparation of[4-chloro-1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-amine(P-0166)

To[1-ethyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine(P-0165, 10.1 mg, 0.0289 mmol, prepared as described in Example 105,Scheme 162) in acetonitrile (8.0 mL) was added N-chloro-succinimide(4.18 mg, 0.0318 mmol). The reaction was stirred at room temperature for2 hours. The reaction was concentrated and purified by silica gel columnchromatography eluting with 20% to 100% ethyl acetate in hexane to givea white solid (P-0166, 1.1 mg). MS (ESI) [M+H⁺]⁺=382.1.

Example 49 Synthesis of5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester

5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester was synthesized in 3 steps as shown in Scheme 164.

Step 1—Preparation of(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-dimethyl-amine (533)

To 5-Chloro-1H-pyrrolo[2,3-b]pyridine (532, 8.00 g, 0.0524 mol) inisopropyl alcohol (250.0 mL) were added dimethylamine hydrochloride(4.79 g, 0.0587 mol) and formaldehyde (1.77 g, 0.0589 mol). The reactionwas stirred at room temperature overnight, followed by refluxing for 4hours. The reaction was concentrated, poured into water, and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated to give crudecompound (533, 10.0 g, 91%), that was used directly in the next step.

Step 2 and 3—Preparation of5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester (535)

5-Chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester 535 was prepared following the protocol of Scheme 158(Example 101) steps 1 and 2, substitutingdimethyl-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine 2 with(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-dimethyl-amine 533 instep 1.

Example 50 Synthesis of(4-chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-amineP-0132

(4-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-amineP-0132 was synthesized in 3 steps as shown in Scheme 165.

Step 1—Preparation of (4-chloro-benzyl)-(6-fluoro-pyridin-2-yl)-amine(536)

To 2,6-difluoropyridine (58, 9.85 g, 0.0856 mol) inN-methylpyrrolidinone (50.0 mL) were added p-chlorobenzylamine (61, 10.5mL, 8.63 mmol) and N,N-diisopropylethylamine (30.0 mL, 0.172 mol). Thereaction was stirred at 90° C. overnight. The reaction was poured intowater and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 25% ethylacetate in hexane, then washed with ethyl acetate/hexane to give a whitesolid (536, 10 g, 50%).

Step 2—Preparation of(5-bromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-amine (537)

To (4-chloro-benzyl)-(6-fluoro-pyridin-2-yl)-amine (536, 1.03 g, 4.35mmol) in acetonitrile (30.0 mL), under an atmosphere of nitrogen,N-bromosuccinimide (0.820 g, 4.61 mol) was added slowly. After 2 hours,the reaction was poured into a solution of sodium thiosulfate andextracted with ethyl acetate. The organic layer was dried over sodiumsulfate, concentrated and crytstallized with ethyl acetate and hexane togive a white solid (537, 1.10 g, 80.1%).

Step 3—Preparation of(4-chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-amine(P-0132)

To (5-bromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-amine (537, 2.76 g,8.75 mol) in tetrahydrofuran (90.0 mL), under an atmosphere of nitrogenat −78° C., n-butyllithium (2.50 M in hexane, 3.64 mL) was added slowly.After 60 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (0.942 g,4.38 mol) in tetrahydrofuran (8.0 mL) was added to the reaction. Thereaction mixture was allowed to stir at room temperature for 2 hours.The reaction was cooled to −78° C., followed by addition oftert-butyllithium (1.70 M in hexane, 10.50 mL). The reaction was stirredfor 30 minutes, followed by addition of 0.65 M of CuCN.2LiCl intetrahydrofuran (14.0 mL). The reaction was stirred at −35° C. for 10minutes, followed by addition of5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester (535, 1.70 g, 5.64 mol, prepared as described inExample 49, Scheme 164) in tetrahydrofuran (10.0 mL). The reaction wasallowed to warm to room temperature for 1 hour and 2 N HCl (30 mL) wasadded to the reaction mixture, then stirred for 30 minutes. The reactionwas poured into aqueous ammonia and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified with silica gel columnchromatography eluting with 30% ethyl acetate in hexane to give thedesired compound (P-0132, 0.75 g, 33.1%). MS (ESI) [M+H]⁺=401.1.

Example 51 Synthesis of5-chloro-3-(2,6-difluoro-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridineP-0155

5-Chloro-3-(2,6-difluoro-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridineP-0155 was synthesized in 1 step as shown in Scheme 166. Scheme 166

Step 1—Preparation of5-chloro-3-(2,6-difluoro-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(P-0155)

To 2,6-Difluoropyridine (58, 3.40 g, 0.0295 mol) in tetrahydrofuran(200.0 mL), under an atmosphere of nitrogen at −78° C., 2.50 M ofn-butyllithium in hexane (12.0 mL) was added slowly. After 60 minutes,CuCN.2LiCl (0.75 M in tetrahydrofuran, 40.0 mL) was added to thereaction mixture. After 5 minutes,5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester (535, 4.20 g, 0.0139 mol, prepared as described inExample 49, Scheme 164) in tetrahydrofuran (20 mL) was added to thereaction. The reaction was stirred at −78° C. overnight, then pouredinto water and ammonia (10 mL), and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 15% ethyl acetate in hexane to give a whitesolid (P-0155, 300 mg, 7.7%). MS (ESI) [M−H⁺]⁻=278.1.

Example 52 Synthesis of3-(2,6-difluoro-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine P-0154

3-(2,6-difluoro-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine P-0154 wassynthesized in 1 step as shown in Scheme 167.

Step 1—Preparation of3-(2,6-difluoro-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (P-0154)

To3-(2,6-difluoro-pyridin-3-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (536, 0.35 g, 1.0 mmol, prepared as described inExample 49, Scheme 164, replacing 5-chloro-1H-pyrrolo[2,3-b]pyridine 532with 1H-pyrrolo[2,3-b]pyridine in step 1) in N-methylpyrrolidinone (3.00mL) were added p-chlorobenzylamine (0.20 mL, 1.6 mmol) andN,N-diisopropylethylamine (0.30 mL, 0.0017 mol). The reaction wasstirred at 50° C. for 72 hours. The reaction was poured into water andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and the crudeintermediate was dissolve in dichloromethane (15.0 mL) andtrifluoroacetic acid (0.5 mL). The reaction was stirred at roomtemperature for 2 hours, then concentrated, poured into aqueouspotassium carbonate, and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 35% ethyl acetate in hexane to give a white solid (P-0154, 0.18 g,72%). MS (ESI) [M+H⁺]⁺=246.2.

Example 53 Synthesis of5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-(4-chlorobenzyl)-6-chloropyridin-2-amineP-0161

5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-(4-chlorobenzyl)-6-chloropyridin-2-amineP-0161 was synthesized in 6 steps as shown in Scheme 168.

Step 1—Preparation of (4-chloro-benzyl)-(6-chloro-pyridin-2-yl)-amine(538)

To 6-chloro-pyridin-2-ylamine (537, 5.60 g, 0.0436 mol) in acetonitrile(300 mL) were added 4-chlorobenzaldehyde (40, 6.7 g, 0.048 mol),trifluoroacetic acid (13 mL, 0.17 mol) and triethylsilane (21 mL, 0.13mol). The reaction was heated to reflux for 4 hours, then concentrated,poured into water, extracted with ethyl acetate, and washed with sodiumbicarbonate and brine. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated. The filtrate was purified withsilica gel column chromatography eluting with 20% to 100% ethyl acetatein hexane to give a white solid (538, 6.5 g, 59%). MS (ESI)[M+H⁺]⁺=255.1.

Step 2—Preparation of(5-bromo-6-chloro-pyridin-2-yl)-(4-chloro-benzyl)-amine (539)

To (4-chloro-benzyl)-(6-chloro-pyridin-2-yl)-amine (538, 4.00 g, 0.0158mol) in acetonitrile (66.7 mL, 1.28 mol) under an atmosphere ofnitrogen, N-bromosuccinimide (2.81 g, 0.0158 mol) in acetonitrile (20mL) was added slowly. The reaction was stirred at room temperatureovernight, then poured into water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulfate, concentrated andcrystallized with ethyl acetate in hexane to give a white solid (539,2.60 g, 95.3%).

Step 3—Preparation of2-chloro-6-(4-chloro-benzylamino)-pyridine-3-carbaldehyde (540)

To (5-bromo-6-chloro-pyridin-2-yl)-(4-chloro-benzyl)-amine (539, 2.60 g,7.83 mmol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogenat −78° C., isopropylmagnesium chloride (2.00 M in tetrahydrofuran, 4.20mL) was added over 10 minutes. The reaction was stirred at −78° C. for20 minutes, then allowed to warm to room temperature for 10 minutes. Thereaction was cooled to −78° C. tert-Butyllithium (1.70 M in hexane, 10.2mL) was added to the reaction over 10 minutes. After 40 minutes,N,N-dimethylformamide (1.80 mL, 0.0232 mol) was added to the reaction.The reaction was stirred at −78° C. for 40 minutes, then allowed to warmto room temperature for another 30 minutes. The reaction mixture waspoured into water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over sodium sulfate, concentrated andpurified by silica gel column chromatography eluting with 35% to 100%ethyl acetate in hexane to give a light yellow solid (540, 1.0 g,45.4%). MS (ESI) [M−H⁺]⁻=279.0.

Step 4—Preparation of(4-chloro-benzyl)-(6-chloro-5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester (541)

To 2-chloro-6-(4-chloro-benzylamino)-pyridine-3-carbaldehyde (540, 0.40g, 1.42 mmol) in dichloromethane (10.0 mL) were added4-dimethylaminopyridine (10.0 mg, 0.082 mmol), di-tert-butyldicarbonate(0.693 g, 3.17 mmol) and triethylamine (0.50 mL, 0.0036 mol). Thereaction was stirred at room temperature overnight, then concentratedand purified by silica gel column chromatography eluting with 20% to100% ethyl acetate in hexane to give the desired compound (541, 0.45 g,83.0%).

Step 5—Preparation of(4-chloro-benzyl)-6-chloro-5-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl-carbamicacid tert-butyl ester (542):

To 1H-Pyrrolo[2,3-b]pyridine (1, 465 mg, 3.93 mmol) in methanol (50 mL)were added sodium hydroxide (0.630 g, 0.0157 mol) and(4-chloro-benzyl)-(6-chloro-5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester (541, 1.5 g, 0.0039 mol). The reaction was stirred atroom temperature overnight, then poured into water and extracted withethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, concentrated and purified with silica gel columnchromatography eluting with 20% to 100% ethyl acetate in hexane to givethe desired compound (542, 1.0 g, 51%). MS (ESI) [M+H⁺]⁺=499.1.

Step 6—Preparation of5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-(4-chlorobenzyl)-6-chloropyridin-2-amine(P-0161)

To(4-chloro-benzyl)-6-chloro-5-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl-carbamicacid tert-butyl ester (542, 1.00 g, 2.00 mmol) in acetonitrile (130.0mL) were added triethylsilane (11.5 mL, 0.0720 mol) and trifluoroaceticacid (5.5 mL, 0.071 mol). The reaction was heated to reflux for 2 hours,then concentrated, poured into aqueous potassium carbonate, andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and washedwith ethyl acetate and hexane to give a light yellow solid (P-0161, 480mg, 62%). MS (ESI) [M+H⁺]⁺=383.1, 385.1.

[6-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amineP-0174

was prepared following the protocol of Scheme 168, substituting4-chloro-benzaldehyde 40 with 6-trifluoromethyl-pyridine-3-carbaldehydein step 1. MS (ESI) [M+H⁺]⁺=418.2.

[6-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amineP-0176

was prepared following the protocol of Scheme 168, substituting4-chloro-benzaldehyde 40 with 6-trifluoromethyl-pyridine-3-carbaldehydein step 1 and 1H-Pyrrolo[2,3-b]pyridine 1 with5-chloro-1H-pyrrolo[2,3-b]pyridine in step 5. MS (ESI) [M+H⁺]⁺=452.0.

{6-Chloro-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-yl}-(6-trifluoromethyl-pyridin-3-ylmethyl)-amineP-0179

was prepared following the protocol of Scheme 168, substituting4-chloro-benzaldehyde 40 with 6-trifluoromethyl-pyridine-3-carbaldehydein step 1 and 1H-Pyrrolo[2,3-b]pyridine 1 with5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (prepared asdescribed in Example 57, Scheme 172) in step 5. MS (ESI) [M+H⁺]⁺=498.0.

Example 54 Synthesis of(3-chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0129

(3-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0129 was synthesized in 1 step as shown in Scheme 169.

Step 1—Preparation of(3-chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0129)

3-(6-bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(6a, mg, 0.023 mmol, prepared as described in Example 2, Scheme 4) wascombined with 3-chlorobenzyl amine (543, 13 mg, 0.093 mmol) in dioxane(0.3 mL). Tris(dibenzylideneacetone)-dipalladium(0) (3 mg),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 3 mg) andsodium tert-butoxide (15 mg) were added. The mixture was heated at 100°C. overnight. Acetic acid (0.1 mL) was added and the solvents removedunder reduced pressure. The remaining residue was dissolved in DMSO andpurified by reverse phase HPLC on a YMC-Pack ODS-A C-18 column (50 mm×10mm ID), eluting with water with 0.1% trifluoroacetic acid and 5-40%acetonitrile with 0.1% trifluoroacetic acid over 13 minutes at a flowrate of 6 mL/minute to provide the desired compound P-0129. MS (ESI)[M+H⁺]⁺=349.1.

Additional compounds were prepared following the protocol of Scheme 169,replacing 3-chlorobenzyl amine 543 with an appropriate amine. Thefollowing compounds were made following this procedure:

-   (4-Morpholin-4-ylmethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0093),-   Pyridin-3-ylmethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0094),-   (5-Methyl-isoxazol-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0095),-   (2-Pyrrolidin-1-yl-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0096),-   [1-(4-Methanesulfonyl-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0097),-   (2-Methoxy-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0098),-   (2-Morpholin-4-yl-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0099),-   ((R)-1-Phenyl-ethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0125),-   (3-Morpholin-4-yl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0126),-   [1-(2-Fluoro-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0127),-   [2-(3-Fluoro-phenyl)-ethyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0128),-   (1-Methyl-1H-imidazol-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0130), and-   (1,5-Dimethyl-1H-pyrazol-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0131).

The following table indicates the amine (Column 2) used in Scheme 169 toprovide the compounds (Column 3). Column 1 provides the compound numberand column 4 the observed mass.

MS(ESI) Compound [M + H⁺]⁺ number Amine Compound observed P-0093

414.3 P-0094

316.3 P-0095

319.9 P-0096

322.3 P-0097

407.1 P-0098

283.5 P-0099

338.3 P-0125

329.1 P-0126

400.3 P-0127

347.1 P-0128

347.1 P-0130

319.1 P-0131

333.1

Example 55 Synthesis of3-chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamideP-0111

3-Chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamideP-0111 was synthesized in 1 step as shown in Scheme 170.

Step 1—Preparation of3-chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide(P-0111)

3-(6-Bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(6a, 10 mg, 0.023 mmol, prepared as described in Example 2, Scheme 4)was combined with 3-chloro-benzamide (544, 15 mg, 0.096 mmol) in dioxane(0.4 mL). Tris(dibenzylideneacetone)-dipalladium(0) (3 mg),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 3 mg), andsodium tert-butoxide (15 mg) were added. Cesium carbonate (20 mg) wasadded and the mixture was heated at 100° C. overnight. Acetic acid (0.1mL) was added and the solvents removed under reduced pressure. Theremaining residue was dissolved in DMSO (0.2 mL) and purified by reversephase HPLC on a YMC-Pack ODS-A C-18 column (50 mm×10 mm ID), elutingwith water with 0.1% trifluoroacetic acid and 5-40% acetonitrile with0.1% trifluoroacetic acid over 13 minutes at a flow rate of 6 mL/minuteto provide the desired compound P-0111. MS (ESI) [M+H⁺]⁺=363.1.

Additional compounds were prepared following the protocol of Scheme 170,replacing 3-chloro-benzamide 544 with an appropriate amide. Thefollowing compounds were made following this procedure:

-   3,4-Dichloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0100),-   2-Chloro-4-fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0101),-   2,5-Dimethyl-2H-pyrazole-3-carboxylic acid    [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide    (P-0102),-   Thiophene-2-carboxylic acid    [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide    (P-0103),-   2-Methoxy-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide    (P-0104),-   N-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide    (P-0105),-   Pyrazine-2-carboxylic acid    [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide    (P-0106),-   Pyridine-2-carboxylic acid    [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide    (P-0107),-   6-Methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-nicotinamide    (P-0108),-   4-Fluoro-3-methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0109),-   5-Methyl-pyrazine-2-carboxylic acid    [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide    (P-0110),-   4-Fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethyl-benzamide    (P-0112),-   N-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethoxy-benzamide    (P-0113),-   N-[5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethyl-benzamide    (P-0114),-   3-Chloro-4-fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0115),-   3,4-Difluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0116),-   2-Chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0117),-   5-Fluoro-2-methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0118),-   2-Fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0119),-   3-Methoxy-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0120),-   3-Fluoro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0121),-   3-Methyl-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide    (P-0122), and-   2-Chloro-N-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide    (P-0123).

The following table indicates the amide (Column 2) used in Scheme 170 toprovide the compounds (Column 3). Column 1 provides the compound numberand column 4 the observed mass.

MS(ESI) Compound [M + H⁺]⁺ number Amine Compound observed P-0100

397.1 P-0101

381.1 P-0102

347.1 P-0103

335.1 P-0104

360.3 P-0105

329.9 P-0106

331.1 P-0107

329.9 P-0108

344.3 P-0109

361.1 P-0110

345.1 P-0112

415.1 P-0113

413.1 P-0114

397.1 P-0115

381.1 P-0116

365.1 P-0117

363.1 P-0118

361.1 P-0119

347.1 P-0120

359.1 P-0121

347.1 P-0122

343.1 P-0123

364.3

Example 56 Synthesis of3,5-dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylicacid 4-methoxy-benzylamide P-0135

3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylicacid 4-methoxy-benzylamide P-0135 was synthesized in 1 step as shown inScheme 171.

Step 1—Preparation of3,5-dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylicacid 4-methoxy-benzylamide (P-0135)

3-(3,5-dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (514, 10 mg, 0.03 mmol) was dissolved indichloromethane (0.5 mL). 1,8-Diazabicylo[5.4.0]unde-7-ene (6 mg, 0.04mmol) was added. 1-Isocyanatomethyl-4-methoxy-benzene (545, 6.5 mg, 0.04mmol) was added. The reaction was allowed to proceed at room temperaturefor 30 minutes. Acetic acid (0.2 mL) was added to the reaction. Thesolvents were removed under reduced pressure. The residue was dissolvedin dimethyl sulfoxide (0.2 mL) and purified by reverse phase HPLC on aPhenomenex column (50 mm×10 mm ID), eluting with water with 0.1%trifluoroacetic acid and 20-100% acetonitrile with 0.1% trifluoroaceticacid over 16 minutes at a flow rate of 6 mL/minute to provide thedesired compound P-0135. MS (ESI) [M+H⁺]⁺=390.3.

Additional compounds were prepared following the protocol of Scheme 171,replacing 1-isocyanatomethyl-4-methoxy-benzene 545 with an appropriateisocyanate or bromide. The following compounds were made following thisprocedure:

-   3-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine    (P-0133),-   2-[3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazol-1-yl]-1-phenyl-ethanone    (P-0134),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 2-chloro-benzylamide (P-0136),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 2-fluoro-benzylamide (P-0137),-   3-[3,5-Dimethyl-1-(5-trifluoromethyl-furan-2-ylmethyl)-1H-pyrazol-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine    (P-0138),-   3-[3,5-Dimethyl-1-(5-methyl-isoxazol-3-ylmethyl)-1H-pyrazol-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine    (P-0139),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 4-chloro-benzylamide (P-0140),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid [2-(4-ethoxy-phenyl)-ethyl]-amide (P-0141),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 3-methoxy-benzylamide (P-0142),-   3-{3,5-Dimethyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrazol-4-ylmethyl}-1H-pyrrolo[2,3-b]pyridine    (P-0143),-   3-[3,5-Dimethyl-1-(4-methyl-2-phenyl-thiazol-5-ylmethyl)-1H-pyrazol-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine    (P-0144),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 2-methoxy-benzylamide (P-0145),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid [2-(2,4-dichloro-phenyl)-ethyl]-amide (P-0146),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid [2-(4-fluoro-phenyl)-ethyl]-amide (P-0147),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid [2-(2-fluoro-phenyl)-ethyl]-amide (P-0148),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid ((S)-1-phenyl-ethyl)-amide (P-0149),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 3-fluoro-benzylamide (P-0150),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 4-fluoro-benzylamide (P-0151),-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 4-methyl-benzylamide (P-0152), and-   3,5-Dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-1-carboxylic    acid 2-methyl-benzylamide (P-0153).

The following table indicates the isocyanate or bromide (Column 2) usedin Scheme 171 to provide the compounds (Column 3). Column 1 provides thecompound number and Column 4 the observed mass.

MS(ESI) Compound Isocyanate or [M + H⁺]⁺ number bromide Compoundobserved P-0133

317.1 P-0134

345.1 P-0136

394.3 P-0137

378.3 P-0138

375.1 P-0139

322.3 P-0140

393.9 P-0141

404.3 P-0142

390.3 P-0143

482.3 P-0144

414.3 P-0145

390.3 P-0146

442.3 P-0147

392.3 P-0148

392.3 P-0149

374.3 P-0150

378.3 P-0151

378.3 P-0152

374.3 P-0153

374.3

Example 57 Synthesis of5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 547

5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 547 wassynthesized in 1 step from 5-bromo-1H-pyrrolo[2,3-b]pyridine 44 as shownin Scheme 172.

Step 1—Preparation of5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (547)

To 5-bromo-7-azaindole (44, 1.04 g, 5.28 mmol) in 1.00 M potassiumcarbonate in water (15.8 mL) and tetrahydrofuran (50.0 mL) were added1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(546, 1.65 g, 7.92 mmol), Tetrakis(triphenylphosphine)palladium(0)(0.305 mg, 0.26 mmol) and tetra-n-butylammonium iodide (0.20 g, 0.53mmol). The reaction mixture was stirred at 70° C. overnight. Thereaction mixture was poured into water and the organic layer was washedwith brine, dried over sodium sulfate, and concentrated. The residue waspurified with silica gel column chromatography eluting with 25% ethylacetate in hexane to provide a light yellow solid (547, 670 mg, 64.0%).MS (ESI)[M+H⁺]⁺=199.4.

Example 58 Synthesis of[2-(4-fluoro-benzylamino)-thiazol-5-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0177

[2-(4-Fluoro-benzylamino)-thiazol-5-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0177 was synthesized in 2 steps as shown in Scheme 173.

Step 1—Preparation of(4-fluoro-benzyl)-[5-(H-pyrrolo[2,3-b]pyridine-3-carbonyl)-thiazol-2-yl]-carbamicacid tert-butyl ester (549)

A mixture of{4-chloro-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-thiazol-2-yl}-pyridin-4-ylmethyl-carbamicacid tert-butyl ester (548, 0.397 g, 0.57 mmol, prepared according tothe protocol of Scheme 159, Example 44, replacing4-(aminomethyl)pyridine 516 with 4-fluoro-benzylamine in step 1,isolated after step 3), triethylsilane (1.0 mL, 6.3 mmol), andtrifluoroacetic acid (0.5 mL, 6 mmol) in acetonitrile (10 mL) wasstirred at 40° C. for 2 hours. The reaction mixture was poured into icewater, extracted with ethyl acetate, washed with sodium bicarbonate andbrine, and dried over sodium sulfate. After removal of solvent, theresidue was purified by silica gel column chromatography eluting withmethanol in dichloromethane to provide the desired compound as a yellowsolid (549, 0.11 g, 9%). MS (ESI) [M−H]⁺=451.10.

Step 2—Preparation of[2-(4-fluoro-benzylamino)-thiazol-5-yl]-(H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0177)

To a solution of(4-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-thiazol-2-yl]-carbamicacid tert-butyl ester (549, 0.11 g, 0.2 mmol) in dichloromethane (2 mL)was added hydrogen chloride (4 M in 1,4-dioxane, 2 mL). The reactionmixture was stirred at room temperature overnight. The reaction mixturewas poured into cold sodium bicarbonate solution, extracted with ethylacetate, washed with brine and dried over magnesium sulfate. Afterremoval of solvents, the residue was washed with ethyl acetate toprovide the desired compound as a yellow solid (P-0177, 9 mg, 10%). MS(ESI) [M+H]=353.12.

Example 59 Synthesis of{2-[(4-chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0178

{2-[(4-Chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0178 was synthesized in 3 steps as shown in Scheme 174.

Step 1—Preparation of 4-chloro-2-[(4-chloro-benzyl)-methy1-amino]-thiazole-5-carbaldehyde (551)

To a solution of (4-chloro-benzyl)-methyl-amine (550, 2 g, 0.01 mol) andN,N-diisopropylethylamine (4 mL, 0.03 mol) in tetrahydrofuran (50 mL)was added 2,4-dichloro-thiazole-5-carbaldehyde (93, 3 g, 0.01 mmol) intetrahydrofuran (20 mL) at room temperature. The reaction mixture wasstirred at room temperature overnight. The reaction mixture was pouredinto ice water, extracted with ethyl acetate, washed with brine, anddried over sodium sulfate. After removal of solvent, the residue wascollected by filtration and washed with hexanes to provide the desiredcompound as a light-yellow solid (551, 3.6 g, 90%).

Step 2—Preparation of{4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(552)

To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(96, 0.82 g, 2.0 mmol) in tetrahydrofuran (5 mL) at −20° C.,isopropylmagnesium chloride (2 M in tetrahydrofuran, 1.1 mL, 2.2 mmol)was added dropwise. The reaction mixture was allowed to warm to 0° C. in10 minutes. The reaction mixture was then cooled to −40° C. To thereaction mixture was added a solution of4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazole-5-carbaldehyde(551, 0.41 g, 1.4 mmol) in tetrahydrofuran (10 mL). The reaction mixturewas allowed to warm to −10° C. in 30 minutes. The reaction mixture waspoured into ice water, extracted with ethyl acetate, washed with brine,and dried over sodium sulfate. After removal of solvent, the residue waspurified by silica gel column chromatography eluting with ethyl acetatein hexanes to provide the desired compound as a yellow solid (552, 0.5g, 60%). MS (ESI) [M+H⁺]⁺=575.29.

Step 3—Preparation of{2-[(4-chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0178)

A mixture of{4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(552, 1 g, 2 mmol), triethylsilane (2 mL, 12 mmol), and trifluoroaceticacid (1 mL, 13 mmol) in acetonitrile (10 mL) was stirred at 40° C. for 2hours. The reaction mixture was poured into ice water, extracted withethyl acetate, washed with sodium bicarbonate and brine, and dried oversodium sulfate. After removal of solvent, the residue was purified bysilica gel column chromatography eluting with methanol indichloromethane to provide the desired compound as a yellow solid(P-0178, 0.17 g, 30%). MS (ESI) [M+H⁺]⁺=383.09.

Example 60 Synthesis of Aldehyde Intermediates

(3-Chloro-pyridin-4-ylmethyl)-(5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester

558 was synthesized in 4 steps from 6-amino-nicotinic acid methyl ester553 as shown in Scheme 175.

Step 1—Synthesis of 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-nicotinicacid methyl ester (555)

To 6-amino-nicotinic acid methyl ester (553, 2.15 g, 0.014 mol) inacetonitrile (60.0 mL) were added 3-chloro-pyridine-4-carbaldehyde (554,2.00 g, 0.014 mol), triethylsilane (11.00 mL, 0.069 mol) andtrifluoroacetic acid (5.00 mL, 0.065 mol). The reaction was stirred at80° C. overnight. The reaction was concentrated, poured into aqueouspotassium carbonate, and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% to 100% ethyl acetate in hexane to give the desired compound(555, 1.5 g, 38.2%). MS (ESI) [M+H⁺]⁺=278.9.

Step 2—Synthesis of6-[(3-Chloro-pyridin-4-ylmethyl)-amino]-pyridin-3-yl-methanol (556)

To 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-nicotinic acid methyl ester(555, 1.00 g, 3.60 mmol) in tetrahydrofuran (120 mL) was added asolution of lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 5.00mL) under an atmosphere of nitrogen at room temperature. The reactionwas stirred at room temperature overnight, followed with addition ofsodium sulfate decahydrate. After 1 hour, the reaction mixture wasfiltered, concentrated, and purified with silica gel columnchromatography eluting with 2% to 20% methanol in dichloromethane togive the desired compound as a white solid (556, 0.5 g, 56%). MS (ESI)[M+H⁺]⁺=250.1.

Step 3—Synthesis of6-[(3-chloro-pyridin-4-ylmethyl)-amino]-pyridine-3-carbaldehyde (557)

To 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-pyridin-3-yl-methanol (556,0.50 g, 2.00 mmol) in tetrahydrofuran (20.0 mL) was added Dess-Martinperiodinane (1.02 g, 2.40 mmol). The reaction was stirred at roomtemperature for 10 minutes, then poured into aqueous potassiumcarbonate, and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated to give crude compound (557, 0.45 g, 91%) that was used inthe next step without further purification.

Step 4—Synthesis of(3-chloro-pyridin-4-ylmethyl)-(5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester (558)

To 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-pyridine-3-carbaldehyde (557,0.45 g, 1.80 mmol) in dichloromethane (20.0 mL) were addeddi-tert-butyldicarbonate (0.65 g, 3.00 mmol), 4-dimethylaminopyridine(0.012 g, 0.010 mmol) and triethylamine (0.28 mL, 2.00 mmol). Thereaction was stirred at room temperature overnight, then concentratedand purified with silica gel column chromatography eluting with 20% to100% ethyl acetate in hexane to give the desired compound (558, 250 mg,40.0%).

(2-Difluoromethoxy-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester 559

was prepared following the protocol of Scheme 175, substituting3-chloro-pyridine-4-carbaldehyde 554 with 2-difluoromethoxy-benzaldehydein Step 1.

[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-carbamicacid tert-butyl ester 560

was prepared following the protocol of Scheme 175, substituting3-chloro-pyridine-4-carbaldehyde 554 with propane-1-sulfonic acid(2,4-difluoro-3-formyl-phenyl)-amide in Step 1. MS (ESI) [M+H⁺]⁺=470.3.

(6-Fluoro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester 565 was synthesized in 4 steps from2,6-Difluoro-nicotinic acid methyl ester 60 as shown in Scheme 176.

Step 1—Synthesis of2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-nicotinic acidmethyl ester (562)

To 2,6-difluoro-nicotinic acid methyl ester (60, 1.82 g, 0.0105 mol,prepared as described in Example 22, Scheme 24, Step 2) inN,N-dimethylformamide (20.0 mL), under an atmosphere of nitrogen at −40°C., C-(6-trifluoromethyl-pyridin-3-yl)-methylamine (561, 1.00 g, 5.68mmol) was added. The reaction was stirred at −40° C., then allowed towarm to room temperature for 2 hours. The reaction was poured into waterand extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 35% to 100%ethyl acetate in hexane to give a white solid (562, 1.40 g, 74.9). MS(ESI) [M+H⁺]⁺=330.1.

Step 2—Synthesis of2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-yl-methanol(563)

To 2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-nicotinicacid methyl ester (562, 1.40 g, 4.25 mmol) in tetrahydrofuran (100.0 mL)under an atmosphere of nitrogen at room temperature, a solution oflithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 10.0 mL) wasadded slowly. The reaction was stirred at room temperature overnight,followed by addition of an appropriate amount of sodium sulfatedecahydrate. After 1 hour, the reaction mixture was filtered andconcentrated to give crude compound (563, 1.2 g, 93.7%) that was used inthe next step without further purification.

Step 3—Synthesis of2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3-carbaldehyde(564)

To2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-yl-methanol(563, 1.20 g, 3.98 mmol) in dichloromethane (40.0 mL) was addedDess-Martin periodinane (1.86 g, 4.38 mmol). The reaction was stirred atroom temperature for 10 minutes, then poured into aqueous sodiumthiosulfate and potassium carbonate, and extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated and purified by silica gel columnchromatography eluting with 20% to 100% ethyl acetate in hexane to givethe desired compound (564, 0.28 g, 23.5%).

Step 4—Synthesis of(6-fluoro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester (565)

To2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3-carbaldehyde(564, 0.28 g, 0.94 mmol) in tetrahydrofuran (10.0 mL) were addeddi-tert-butyldicarbonate (0.245 g, 1.12 mmol) and4-dimethylaminopyridine (0.050 g, 0.41 mmol). The reaction was stirredat room temperature overnight, then concentrated and purified withsilica gel column chromatography eluting with 20% to 100% ethyl acetatein hexane to give the desired compound (565, 0.22 g, 59%).

(6-Chloro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester 570 was synthesized in 4 steps from6-chloro-pyridin-2-ylamine 537 as shown in Scheme 177.

Step 1—Synthesis of(6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine(567)

To 6-chloro-pyridin-2-ylamine (537, 0.760 g, 5.91 mmol) in acetonitrile(30.0 mL), 6-trifluoromethyl-pyridine-3-carbaldehyde (566, 1.06 g, 6.05mmol), trifluoroacetic acid (3.00 mL, 0.0389 mol) and triethylsilane(6.00 mL, 0.0376 mol) were added. The reaction was heated to reflux for4 hours. The reaction was concentrated, poured into aqueous potassiumcarbonate, and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated and purifiedwith silica gel column chromatography eluting with 20% to 100% ethylacetate in hexane to give a white solid (567, 1.60 g, 94.1%).

Step 2—Synthesis of(5-bromo-6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine(568)

To (6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine(567, 4.50 g, 0.0156 mol) in acetonitrile (120.0 mL) under an atmosphereof nitrogen, N-bromosuccinimide (3.03 g, 0.0170 mol) in acetonitrile (50mL) was added slowly. The reaction was stirred at room temperatureovernight, then poured into water, and extracted with ethyl acetate. Theorganic layer was dried over sodium sulfate, concentrated and purifiedwith silica gel column chromatography eluting with 25% to 100% ethylacetate in hexane to give a white solid (568, 6.20 g, 80.2%).

Step 3—Synthesis of2-chloro-6-[(6-trifluoromethyl-pyridine-3-ylmethyl)-amino]-pyridine-3-carbaldehyde(569)

To(5-bromo-6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine(568, 4.60 g, 0.0125 mol) in tetrahydrofuran (60.0 mL) under anatmosphere of nitrogen at −78° C., isopropylmagnesium chloride (2.00 Min tetrahydrofuran, 6.44 mL) was added over minutes. The reaction wasstirred at −78° C. for 20 minutes, and then allowed to warm to roomtemperature for 10 minutes. The reaction was cooled to −78° C., followedby adding tert-butyllithium (1.70 M in hexane, 15.3 mL) over 10 minutes.After 40 minutes, N,N-dimethylformamide (1.23 mL, 0.0158 mol) was addedand the reaction was stirred at −78° C. for 40 minutes, then allowed towarm to room temperature for 30 minutes. The reaction mixture was pouredinto water and extracted with ethyl acetate. The organic layer waswashed with brine, dried over sodium sulfate, concentrated and purifiedby silica gel column chromatography eluting with 35% to 100% ethylacetate in hexane to give a light yellow solid (569, 2.84 g, 71.7%).

Step 4—Synthesis of(6-chloro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester (570)

To a solution of2-chloro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3-carbaldehyde(569, 0.545 g, 1.73 mmol) in tetrahydrofuran (10 mL),N,N-diisopropylethylamine (0.60 mL, 3.40 mmol), 4-dimethylaminopyridine(20 mg, 0.10 mmol), and a solution of di-tert-butyldicarbonate (0.41 g,0.0019 mol) were added. The reaction mixture was stirred at roomtemperature overnight, then concentrated, poured into water, andextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate, concentrated and purified by silica gelcolumn chromatography eluting with 20% to 100% ethyl acetate in hexaneto give the desired compound (570, 0.60 g, 83.6%).

(5-Bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-amine 571

was prepared following the protocol of Steps 1 and 2 of Scheme 177,substituting 6-chloro-pyridin-2-ylamine 537 and6-trifluoromethyl-pyridine-3-carbaldehyde 566 with6-fluoro-pyridin-2-ylamine and 2-chloro-benzaldehyde, respectively inStep 1.

(6-Fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester 572

was prepared following the protocol of Scheme 177, substituting6-chloro-pyridin-2-ylamine 537 and6-trifluoromethyl-pyridine-3-carbaldehyde 566 with6-fluoro-pyridin-2-ylamine and 6-methoxy-pyridine-3-carbaldehyde,respectively in step 1.

(5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester 631

was prepared following the protocol of Scheme 177, substituting6-chloro-pyridin-2-ylamine 537 and6-trifluoromethyl-pyridine-3-carbaldehyde 566 with6-fluoro-pyridin-2-ylamine and 5-fluoro-pyridine-3-carbaldehyde,respectively in Step 1, without Step 3 (i.e. the product of Step 2 isreacted according to Step 4).

(5-Bromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-carbamic acidtert-butyl ester 637

was prepared following the protocol of Scheme 177, substituting6-chloro-pyridin-2-ylamine 537 and6-trifluoromethyl-pyridine-3-carbaldehyde 566 with6-fluoro-pyridin-2-ylamine and 5-chloro-benzaldehyde, respectively inStep 1, without Step 3 (i.e. the product of Step 2 is reacted accordingto Step 4).

Example 61 Synthesis of propane-1-sulfonic acid(2,4-difluoro-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl-phenyl)-amideP-0258

Propane-1-sulfonic acid(2,4-difluoro-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl-phenyl)-amideP-0258 was synthesized in 2 steps from3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 96 as shown inScheme 178.

Step 1—Synthesis of[2,6-difluoro-3-(propane-1-sulfonylamino)-benzyl]-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl-carbamicacid tert-butyl ester (574)

To a solution of 3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine(96, 0.644 g, 1.61 mmol) in tetrahydrofuran (10.0 mL) at −40° C. undernitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.80mL) was added slowly. The reaction was allowed to warm to 15° C. over100 minutes, then cooled to −40° C., followed by adding[2,6-difluoro-3-(propane-1-sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-carbamicacid tert-butyl ester (560, 0.100 g, 0.21 mmol, prepared as described inExample 60, Scheme 175) in tetrahydrofuran (2.0 mL). The reaction wasallowed to warm to 5° C. over 2 hours, then poured into aqueous ammoniumchloride, and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% to 100% ethyl acetate in hexane to give a yellow solid (574, 75mg, 47%). MS (ESI) [M+H⁺]⁺=744.7.

Step 2—Synthesis of Propane-1-sulfonic acid(2,4-difluoro-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl-phenyl)-amide(P-0258)

To[2,6-difluoro-3-(propane-1-sulfonylamino)-benzyl]-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl-carbamicacid tert-butyl ester (574, 75.0 mg, 0.10 mmol) in acetonitrile (10.0mL) were added triethylsilane (0.40 mL, 2.5 mmol) and trifluoroaceticacid (0.20 mL, 2.6 mmol). The reaction was stirred at 80° C. for 4hours. The reaction was poured into aqueous potassium carbonate, andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 2% to 15% methanol indichloromethane to give an off-white solid (P-0258, 29.3 mg, 61.6%).

MS (ESI) [M+H⁺]⁺=472.4.

Propane-1-sulfonic acid(3-{[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-2,4-difluoro-phenyl)-amide(P-0259),[6-Fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine(P-0378), and

-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine    (P-0379),

respectively,were prepared following the protocol of Scheme 178. P-0259 was preparedby replacing 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 96with 5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine inStep 1 (MS [M+H⁺]⁺=506.1). P-0378 was prepared by replacing[2,6-difluoro-3-(propane-1-sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-carbamicacid tert-butyl ester 560 with(6-Fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester 572 (prepared as described in Example 60, Scheme177) in Step 1 (MS [M+H⁺]⁺=364.1). P-0379 was prepared by replacing bothazaindole 96 with5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine andaldehyde 560 with aldehyde 572 in Step 1 (MS [M+H⁺]⁺=400.0).

Example 62 Synthesis of[6-fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amineP-0187

[6-Fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amineP-0187 was synthesized in 3 steps from1-benzenesulfonyl-3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine 575 asshown in Scheme 179.

Step 1—Synthesis of5-[(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester (576)

To 1-benzenesulfonyl-3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine (575,0.326 g, 0.000788 mol) in tetrahydrofuran (3.00 mL) at −45° C. undernitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.380mL) was added slowly. The reaction was allowed to warm to −25° C. in 30minutes, and then cooled to −45° C. followed by adding(6-fluoro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester (565, 80.0 mg, 0.20 mmol, prepared as described inExample 60, Scheme 176) in tetrahydrofuran (1.0 mL). The reaction wasallowed to warm to room temperature over 2 hours. The reaction waspoured into aqueous ammonium chloride, and extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated and purified by silica gel columnchromatography eluting with 20% to 100% ethyl acetate in hexane to givethe desired compound (576, 0.080 g, 60%). MS (ESI) [M+H⁺]⁺=688.1.

Step 2—Synthesis of[5-(1-Benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine(577)

To5-[(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester (576, 0.100 g, 0.15 mmol) in acetonitrile (12.6mL) were added triethylsilane (0.34 mL, 2.10 mmol) and trifluoroaceticacid (0.17 mL, 2.20 mmol). The reaction was heated to 80° C. for 2hours. The reaction was poured into aqueous potassium carbonate, andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated to give thecrude compound (577, 90 mg, 100%) that was used in the next step withoutfurther purification.

Step 3—Synthesis of[6-Fluoro-5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine(P-0187)

To[5-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine(577, 0.08 g, 0.13 mmol) in tetrahydrofuran (10.0 mL) was addedtetrabutylammonium fluoride, trihydrate (0.110 g, 0.35 mmol). Thereaction was stirred at room temperature overnight, then poured intowater, and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% to 100% ethyl acetate in hexane to give an off-white solid(P-0187, 8.1 mg, 10%). MS (ESI) [M+H⁺]⁺=431.9.

[6-Fluoro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amineP-0186 and[6-Fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amineP-0188,

were prepared following the protocol of Scheme 179, substituting1-benzenesulfonyl-3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine 575 with1-benzenesulfonyl-3-iodo-5-chloro-1H-pyrrolo[2,3-b]pyridine or1-Benzenesulfonyl-3-iodo-1H-pyrrolo[2,3-b]pyridine, respectively, inStep 1. MS (ESI) [M+H⁺]⁺=435.7 and 401.6, respectively.

Example 63 Synthesis of[6-(2-fluoro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0403

[6-(2-fluoro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0403 was synthesized in 2 steps from3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 96 as shown inScheme 180.

Step1—(2-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-carbamicacid tert-butyl ester (580)

To 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 0.550 g,1.37 mmol) in tetrahydrofuran (15.0 mL) at −40° C. under nitrogen,isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.65 mL) wasadded slowly. The reaction was allowed to warm to 5° C. over 70 minutes,then cooled to −40° C., followed by adding(2-fluoro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester(579, prepared according to the protocol of Example 17, Scheme 19, Steps1-3, replacing 4-chlorobenzaldehyde 40 with 2-fluoro-benzaldehyde inStep 1) in tetrahydrofuran (4.0 mL). The reaction was allowed to warm toroom temperature over 1 hour, then poured into aqueous ammoniumchloride, and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% to 100% ethyl acetate in hexane to give the desired compound(580, 0.14 g, 26%). MS (ESI) [M+H⁺]⁺=447.0.

Step 2—Synthesis of[6-(2-Fluoro-benzylamino)-pyridin-3-yl]-(H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-0403)

To(2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-carbamicacid tert-butyl ester (580, 0.080 g, 0.18 mmol) in dichloromethane (3.0mL) was added trifluoroacetic acid (1.0 mL, 0.013 mol). The reaction wasstirred at room temperature overnight, then concentrated, poured intowater, and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 2% to 15% methanol in dichloromethane to give the desired compound(P-0403, 15.0 mg, 23.0%). MS (ESI) [M+H⁺]⁺=347.5.

Example 64 Synthesis of(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(2-fluoro-benzylamino)-pyridin-3-yl]-methanoneP-0404

(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(2-fluoro-benzylamino)-pyridin-3-yl]-methanoneP-0404 was synthesized in 4 steps from1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 581 as shownin Scheme 181.

Step 1—Synthesis of5-[(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl-(2-fluoro-benzyl)-carbamicacid tert-butyl ester (582)

To a solution of1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (581, 0.420g, 1.00 mmol) in tetrahydrofuran (15.0 mL) at −40° C. under nitrogen,isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.49 mL) wasadded slowly. The reaction was allowed to warm to 5° C. over 70 minutes,then cooled to −40° C., followed by adding(2-fluoro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester579 in tetrahydrofuran (6.0 mL). The reaction was allowed to warm toroom temperature over 1 hour, then poured into aqueous ammoniumchloride, and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% to 100% ethyl acetate in hexane to give the desired compound(582, 0.25 g, 41%). MS (ESI) [M+H⁺]=623.1.

Step 2—Synthesis of[5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(2-fluoro-benzyl)-carbamicacid tert-butyl ester (583)

To5-[(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl-(2-fluoro-benzyl)-carbamicacid tert-butyl ester (582, 0.25 g, 0.40 mmol) in dichloromethane (5.0mL) was added Dess-Martin periodinane (0.20 g, 0.48 mmol). The reactionwas stirred at room temperature for 10 minutes, then poured into aqueouspotassium carbonate, and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% to 100% ethyl acetate in hexane to give the desired compound(583, 0.060 g., 24%).

Step 3—Synthesis of[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(2-fluoro-benzyl)-carbamicacid tert-butyl ester (584)

To[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(2-fluoro-benzyl)-carbamicacid tert-butyl ester (583, 60.0 mg, 0.097 mmol) in tetrahydrofuran (1.0mL) was added aqueous potassium carbonate (1.0 M, 1.0 mL). The reactionwas irradiated with microwave on 300 watts, 100° C. for 10 minutes, thenpoured into water and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated to give crude compound (584, 0.040 g, 64%) that was used inthe next step without further purification.

Step 4—Synthesis of(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(2-fluoro-benzylamino)-pyridin-3-yl]-methanone(P-0404)

To[5-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(2-fluoro-benzyl)-carbamicacid tert-butyl ester (584, 0.030 g, 0.062 mmol) in dichloromethane (1.0mL) was added trifluoroacetic acid (1.0 mL, 0.013 mol). The reaction wasstirred at room temperature overnight, then poured into aqueouspotassium carbonate, and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 2% to 15% methanol in dichloromethane to give the desired compound(P-0404, 2.8 mg, 12%). MS (ESI) [M+H⁺]⁺=381.0.

Example 65 Synthesis of(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-[(6-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-yl-methanoneP-0405

(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-[(6-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-yl-methanoneP-0405 was synthesized in 3 steps from5-Chloro-1H-pyrrolo[2,3-b]pyridine 532 as shown in Scheme 182.

Step 1—Synthesis of5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl-(6-methoxy-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester (586)

To 5-chloro-1H-pyrrolo[2,3-b]pyridine (532, 0.092 g, 0.60 mmol) inmethanol (15.0 mL) were added(5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acidtert-butyl ester (585, 0.240 g, 0.70 mmol, prepared according to theprotocol of Example 17, Scheme 19, Steps 1-3, replacing4-chlorobenzaldehyde 40 with 6-methoxy-pyridine-3-carbaldehyde inStep 1) and potassium hydroxide (1.2 g, 0.021 mol). The reaction wasstirred at room temperature overnight, then poured into water, andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 20% to 100% ethylacetate in hexane to give the desired compound (586, 0.110 g, 37%).

Step 2—Synthesis of[5-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester (587)

To5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl-(6-methoxy-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester (586, 0.060 g, 0.12 mmol) in dichloromethane (10.0mL) was added Dess-Martin periodinane (0.062 g, 0.15 mmol). The reactionwas stirred at room temperature for 10 minutes. The reaction wasconcentrated and purified by silica gel column chromatography elutingwith 20% to 100% ethyl acetate in hexane to give the desired compound(587, 0.020 g, 33%).

Step 3—Synthesis of(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-[(6-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-yl-methanone(P-0405)

To[5-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester (587, 0.020 g, 0.040 mmol) in dichloromethane (2.0mL) was added trifluoroacetic acid (0.30 mL, 0.0039 mol). The reactionwas stirred at room temperature for 2 hours, then poured into aqueouspotassium carbonate, and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% to 100% ethyl acetate in hexane to give the desired compound(P-0405, 5.5 mg, 34%). MS (ESI) [M+H⁺]⁺=394.3.

{6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-yl}-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-0406

was prepared following the protocol of Scheme 182, substituting5-chloro-1H-pyrrolo[2,3-b]pyridine 532 with5-methoxy-1H-pyrrolo[2,3-b]pyridine in step 1. MS (ESI) [M+H⁺]⁺=390.1.

Example 66 Synthesis of intermediate5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine592

5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine592 was synthesized in 4 steps from2-amino-4-chloro-thiazole-5-carbaldehyde 588 as shown in Scheme 183.

Step 1—Synthesis of (4-chloro-5-formyl-thiazol-2-yl)-carbamic acidtert-butyl ester (589)

To 2-amino-4-chloro-thiazole-5-carbaldehyde (588, 5.00 g, 0.0308 mol) intetrahydrofuran (122 mL) were added di-tert-butyldicarbonate (7.38 g,0.0338 mol) and 4-dimethylaminopyridine (0.35 g, 0.0029 mol). Thereaction was stirred at 58° C. for 2 hours, then concentrated andpurified with silica gel column chromatography eluting with 20% to 80%ethyl acetate in hexane to give a yellow solid (589, 7.0 g, 87%).

Step 2—Synthesis of5-[(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-4-chloro-thiazol-2-yl-carbamicacid tert-butyl ester (590)

To a solution of1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (581, 4.40g, 10.5 mmol) in tetrahydrofuran (30.0 mL) at −45° C. under nitrogen, asolution of isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 5.4mL) was added slowly over 10 minutes. The reaction was allowed to warmto −25° C. over 30 minutes. The reaction was cooled to −65° C., followedby adding the cold deprotonated(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester 589,which was prepared in situ by adding isopropylmagnesium chloride (2.0 Min tetrahydrofuran, 5.0 mL) to (4-chloro-5-formyl-thiazol-2-yl)-carbamicacid tert-butyl ester (589, 2.51 g, 9.55 mmol) in tetrahydrofuran (23.0mL) at −78° C. under an atmosphere of nitrogen. The reaction was allowedto warm to room temperature in 2 hours, then poured into aqueousammonium chloride, and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 25% to 100% ethyl acetate in hexane to give the desired compound(590, 3.70 g, 60.3%). MS (ESI) [M+H⁺]⁺=554.2.

Step 3—Synthesis of[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-carbamicacid tert-butyl ester (591)

To5-[(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-4-chloro-thiazol-2-yl-carbamicacid tert-butyl ester (590, 0.200 g, 0.32 mmol) in dichloromethane (15.0mL) were added triethylsilane (0.600 mL, 376 mmol) and trifluoroaceticacid (0.300 mL, 3.89 mmol). The reaction was stirred at room temperaturefor 3 hours, then concentrated, poured into aqueous potassium carbonate,and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 25% to 100%ethyl acetate in hexane to give the desired compound (591, 0.155 g,88.7%). MS (ESI) [M+H⁺]⁺=538.9.

Step 4—Synthesis of5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine(592)

To[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-carbamicacid tert-butyl ester (591, 4.30 g, 7.97 mmol) in dichloromethane (70.0mL) was added a solution of hydrogen chloride (4.00 M in 1,4-dioxane,42.0 mL). The reaction was stirred at room temperature for 2 days, thenconcentrated, and triturated with ethyl ether and ethyl acetate to givethe desired compound (592, 2.60 g, 74.2%). MS (ESI) [M+H⁺]⁺=439.0.

5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine593

was prepared following the protocol of Scheme 183, substituting1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 581 with1-benzenesulfonyl-3-iodo-1H-pyrrolo[2,3-b]pyridine in Step 2. MS (ESI)[M+H⁺]⁺=404.4.

Example 67 Synthesis of[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amineP-0231

[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amineP-0231 was synthesized in 2 steps from5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine592 as shown in Scheme 184.

Step 1—Synthesis of[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine(595)

To5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine(592, 50.0 mg, 0.11 mmol, prepared as described in Example 66, Scheme183) in ethanol (1.60 mL) and acetic acid (0.08 mL) were added5-fluoro-pyridine-3-carbaldehyde (594, 43 mg, 0.34 mmol) and silicasupported cyanoborohydride (1.21 mmol/g, 0.180 g). The reaction wasirradiated with microwave on 300 watts, 100° C. for 7 minutes. Thereaction was poured into aqueous potassium carbonate, and extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 20% ethyl acetate in hexane to givethe desired compound (595, 0.030 g, 48%).

Step 2—Synthesis of[4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine(P-0231)

To[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine(595, 0.030 g, 0.055 mmol) in tetrahydrofuran (6.0 mL) was addedtetrabutylammonium fluoride, trihydrate (0.034 g, 0.11 mmol) under anatmosphere of nitrogen. The reaction was stirred at room temperature for3 hours, then poured into water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 20% to 100% ethyl acetate in hexane to givethe desired compound (P-0231, 1.5 mg, 6.7%). MS (ESI) [M+H⁺]⁺=408.1.

Example 68 Synthesis of5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine599

5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine599 was synthesized in 4 steps from 5-chloro-1H-pyrrolo[2,3-b]pyridine532 as shown in Scheme 185.

Step 1—Synthesis of 5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde(596)

To 5-chloro-1H-pyrrolo[2,3-b]pyridine (532, 10.0 g, 65.5 mmol) in aceticacid (28.3 mL) were added hexamethylenetetramine (11.9 g, 85.2 mmol) andwater (56.7 mL). The reaction was refluxed overnight, followed byaddition of 200 mL of water. After 30 minutes, the reaction was filteredto recover the solid, then dried under air to give the desired compound(596, 7.0 g. 59%).

Step 2—Synthesis of1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde(597)

To 5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (596, 3.60 g,0.0199 mol) in dichloromethane (100 mL) were added a solution ofpotassium hydroxide (9 M in water, 50 mL), tetrabutylammonium hydrogensulfate (400 mg, 0.001 mol) and benzenesulfonyl chloride (2.9 mL, 0.023mol). The reaction was stirred at room temperature for 3 hours, thenpoured into water and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and washed with ethyl acetate to give a white solid (597,2.3 g, 36.0%).

Step 3—Synthesis of(6-amino-pyridin-3-yl)-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(598)

To 2-amino-5-bromopyridine (15, 3.10 g, 17.9 mmol) in tetrahydrofuran(80.0 mL) under an atmosphere of nitrogen at −78° C., a solutionn-butyllithium (2.50 M in hexane, 7.10 mL) was added slowly. After 30minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (3.90 g dissolved intetrahydrofuran 20.0 mL, 18.1 mmol) was added to the reaction mixtureslowly, and then allowed to warm to room temperature for 1 hour. Thereaction was cooled to −78° C. followed by adding a solution ofn-butyllithium (2.50 M in Hexane, 7.10 mL). The reaction mixture wasstirred at −78° C. for 30 minutes, then allowed to warm to roomtemperature for 60 minutes. The reaction mixture was cooled to −78° C.,followed by adding a solution of n-butyllithium (2.50 M in Hexane, 7.50mL) slowly. After 60 minutes,1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde(597, 1.90 g in 30 mL tetrahydrofuran, 5.92 mmol) was added to thereaction mixture. The reaction mixture was stirred at −78° C. for 2hours, then allowed to warm to room temperature for 1 hour. The reactionwas poured into water and extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated and purified by silica gel column chromatographyeluting with 2% to 20% methanol in dichloromethane to give the desiredcompound (598, 1.25 g, 50.9%). MS (ESI) [M+H⁺]⁺=415.2.

Step 4—Synthesis of5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine(599)

To(6-amino-pyridin-3-yl)-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(598, 1.00 g, 0.00241 mol) in dichloromethane (25.0 mL) were addedtriethylsilane (3.00 mL, 0.0188 mol) and trifluoroacetic acid (1.50 mL,0.0195 mol). The reaction was stirred at room temperature overnight,then concentrated, poured into aqueous potassium carbonate, andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 20% to 100% ethylacetate in hexane to give the desired compound (599, 0.70 g, 73%).

[0764]5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine600

was prepared following the protocol of Scheme 185, substituting5-chloro-1H-pyrrolo[2,3-b]pyridine 532 with 1H-pyrrolo[2,3-b]pyridine inStep 1. MS (ESI) [M+H⁺]⁺=365.2.

Example 69 Synthesis of[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amineP-0324

[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amineP-0324 was synthesized in 2 steps from5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine599 as shown in Scheme 186.

Step 1—Synthesis of[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine(601)

To5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine(599, 80.0 mg, 0.20 mmol, prepared as described in Example 68, Scheme185) in ethanol (2.0 mL) and acetic acid (0.10 mL, 0.0018 mol) wereadded 5-fluoro-pyridine-3-carbaldehyde (594, 62.7 mg, 0.50 mmol) andsodium cyanoborohydride on silica gel (1.200 mmol/g loading; 0.251 g,0.30 mmol). The reaction was irradiated with microwave on 300 watts,100° C. for 10 minutes. The reaction was poured into aqueous potassiumcarbonate and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% to 100% ethyl acetate in hexane to give the desired compound(601, 0.060 g, 59%).

Step 2—Synthesis of[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine(P-0324)

To[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine(601, 0.060 g, 0.12 mmol) in tetrahydrofuran (10.0 mL) was addedtetrabutylammonium fluoride, trihydrate (0.11 g, 0.35 mmol). Thereaction was stirred at room temperature overnight, then poured intowater and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 20% to 100%ethyl acetate in hexane to give the desired compound (P-0324, 13.5 mg,31%). MS (ESI) [M+H⁺]⁺=368.0.

Example 70 Synthesis of(3-Chloro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0183

(3-Chloro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0183 was synthesized in 2 steps from5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine600 as shown in Scheme 187.

Step 1—Synthesis of[5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-pyridin-3-ylmethyl)-amine(602)

To5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine(600, 120.0 mg, 0.33 mmol, prepared as described in Example 68, Scheme185) in acetonitrile (10.0 mL) were added3-chloro-pyridine-4-carbaldehyde (554, 51.3 mg, 0.36 mmol),trifluoroacetic acid (0.30 mL, 0.0039 mol) and triethylsilane (0.60 mL,0.0038 mol). The reaction was heated to reflux overnight, then pouredinto aqueous potassium carbonate and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 30% to 100% ethyl acetate in hexane to givethe desired compound (602, 80 mg, 49.6%). MS [M+H]=490.2.

Step 2—Synthesis of(3-chloro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0183)

To[5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-pyridin-3-ylmethyl)-amine(602, 0.08 g, 0.16 mmol) in tetrahydrofuran (10.0 mL) was addedtetrabutylammonium fluoride, trihydrate (0.240 g, 0.76 mmol). Thereaction was stirred at room temperature overnight. The reaction wasconcentrated and purified by silica gel column chromatography elutingwith 20% to 100% ethyl acetate in hexane to give a yellow solid (P-0183,4.0 mg, 7%). MS (ESI) [M+H⁺]⁺=350.2.

Example 71 Synthesis of[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-amineP-0409

[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amineP-0409 was synthesized in 1 step from5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine599 as shown in Scheme 188.

Step 1—Synthesis of[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-amine(P-0409)

To5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine(599, 124.1 mg, 0.31 mmol, prepared as described in Example 68, Scheme185) in ethanol (3.00 mL) and acetic acid (0.2 mL) were added6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbaldehyde (603, 164.0 mg, 0.80mmol) and silica supported cyanoborohydride (1.21 mmol/g, 0.700 g). Thereaction was irradiated with microwave on 300 watts, 100° C. for 150minutes. To the reaction was added a solution of potassium hydroxide(9.0 M in water, 1.0 mL). The reaction was irradiated with microwave on300 watts, 100° C. for 10 minutes. The reaction was poured into aqueouspotassium carbonate and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% to 100% ethyl acetate in hexane to give the desired compound(P-0409, 10.6 mg, 7.6%). MS ESI) [M+H⁺]⁺=448.4.

Example 72 Synthesis of1-(3-fluoro-phenyl)-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-ureaP-0412

1-(3-Fluoro-phenyl)-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-ureaP-0412 was synthesized in 2 steps from5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine600 as shown in Scheme 189.

Step 1—Synthesis of1-[5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-(3-fluoro-phenyl)-urea(605)

To5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine(600, 150.0 mg, 0.41 mmol, prepared as described in Example 68, Scheme185) in acetonitrile (12.5 mL) were added 3-fluoro-isocyanato-benzene(604, 61.6 mg, 0.45 mmol), 4-dimethylaminopyridine (10.0 mg, 0.082 mmol)and triethylamine (0.25 mL, 0.0018 mol). The reaction mixture was heatedat 70° C. overnight, then poured into water, and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 20% to 100% ethyl acetate in hexaneto give a white solid (605, 0.100 g, 48.4%).

Step 2—Synthesis of1-(3-Fluoro-phenyl)-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-urea(P-0412)

To1-[5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-(3-fluoro-phenyl)-urea(605, 0.100 g, 0.20 mmol) in tetrahydrofuran (10.0 mL) was addedtetrabutylammonium fluoride, trihydrate (0.240 g, 0.76 mmol). Thereaction was stirred at room temperature for 5 hours, then poured intowater, and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 20% to 100% ethyl acetate in hexane to give a white solid (P-0412,17.9 mg, 24.8%). MS (ESI) [M+H]=362.2.

Example 73 Synthesis of(2-chloro-benzyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0335

(2-Chloro-benzyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0335 was synthesized in 2 steps from(5-bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-amine 571 as shown inScheme 190.

Step 1—Synthesis of[6-(2-chloro-benzylamino)-2-fluoro-pyridin-3-yl]-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(606)

To (5-bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-amine (571, 0.635g, 2.01 mmol, prepared as described in Example 60, Scheme 177) intetrahydrofuran (25.0 mL) under an atmosphere of nitrogen at −78° C., asolution of n-butyllithium (2.50 M in hexane, 0.80 mL) was added slowly.After 20 minutes, tert-butyllithium (1.7 M in hexane, 2.40 mL) was addedto the reaction and after 30 minutes,1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (47,0.575 g, 1.90 mmol, prepared as described in Example 18) intetrahydrofuran (8.0 mL) was added to the reaction. The reaction mixturewas stirred at −78° C. for 60 minutes, then allowed to warm to roomtemperature for another 10 minutes. The reaction mixture was poured intoaqueous ammonium chloride and extracted with ethyl acetate. The organiclayer was washed with brine, dried over sodium sulfate, concentrated andpurified by silica gel column chromatography eluting with 20% to 100%ethyl acetate in hexane to give the desired compound (606, 0.180 g,17.6%). MS (ESI) [M+H⁺]⁺=539.2.

Step 2—Synthesis of(2-chloro-benzyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0335)

To[6-(2-chloro-benzylamino)-2-fluoro-pyridin-3-yl]-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(606, 180.0 mg, 0.33 mmol) in acetonitrile (15.0 mL) were addedtriethylsilane (1.00 mL, 6.26 mmol) and trifluoroacetic acid (0.50 mL,6.50 mmol). The reaction was heated to reflux for 2 hours, then pouredinto aqueous potassium carbonate and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 20% to 100% ethyl acetate in hexane to givea white solid (P-0335, 24.9 mg, 19.4%). MS (ESI) [M+H⁺]⁺=367.0.

Example 74 Synthesis of1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine610

1-Benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine610 was synthesized in 3 steps from1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 581 as shownin Scheme 191.

Step 1—Synthesis of(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-methylsulfanyl-pyrimidin-5-yl)-methanol(608)

To a solution of1-Benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (581, 4.36g, 10.4 mmol) in tetrahydrofuran (100.0 mL) at −40° C. under nitrogen,isopropylmagnesium chloride (2.0 M in tetrahydrofuran. 5.06 mL) wasadded slowly. The reaction was allowed to warm to 5° C. over 60 minutes,then cooled to −40° C., followed by adding2-methylsulfanyl-pyrimidine-5-carbaldehyde (607, 1.30 g, 8.43 mmol,dissolved in tetrahydrofuran 15.0 mL). The reaction was allowed to warmto 10° C. over 2 hours. The reaction was poured into aqueous ammoniumchloride and extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated and purified by silica gel column chromatography elutingwith 2% to 15% methanol in dichloromethane to give the desired compound(608, 3.00 g, 79.6%). MS (ESI) [M+H⁺]⁺=447.2.

Step 2—Synthesis of1-benzenesulfonyl-5-chloro-3-(2-methylsulfanyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(609)

To(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-methylsulfanyl-pyrimidin-5-yl)-methanol(608, 0.35 g, 0.78 mmol) in dichloromethane (15.0 mL) were addedtriethylsilane (2.00 mL, 12.52 mmol) and trifluoroacetic acid (1.00 mL,13.0 mmol). The reaction was stirred at 35° C. overnight, thenconcentrated, poured into aqueous potassium carbonate, and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated and purified bysilica gel column chromatography eluting with 20% to 100% ethyl acetatein hexane to give the desired compound (609, 0.25 g, 74%). MS (ESI)[M+H⁺]⁺=430.9.

Step 3—Synthesis of1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(610) and1-benzenesulfonyl-5-chloro-3-(2-methanesulfinyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(611)

To1-benzenesulfonyl-5-chloro-3-(2-methylsulfanyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(609, 0.500 g, 1.16 mmol) in dichloromethane (15.0 mL) was addedmeta-chloroperoxybenzoic acid (max. 77%, 0.572 g, 2.55 mmol) at 0° C.The reaction was stirred at 0° C. for 70 minutes, then poured into waterand extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 20% to 100%ethyl acetate in hexane to give the desired compounds (610, 0.310 g,57.7%), MS (ESI) [M+H⁺]⁺=463.1; and (611, 0.200 g, 38.6%), MS (ESI)[M+H⁺]⁺=447.2.

1-Benzenesulfonyl-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine612

was prepared following the protocol of Scheme 191, substituting1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 581 with1-benzenesulfonyl-3-iodo-1H-pyrrolo[2,3-b]pyridine in Step 1.

Example 75 Synthesis of(4-chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amineP-0260

(4-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amineP-0260 was synthesized in 2 steps from1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine610 as shown in Scheme 192.

Step 1—Synthesis of[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-chloro-benzyl)-amine(613)

To1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(610, 0.060 g, 0.13 mmol, prepared as described in Example 74, Scheme191) in N-methylpyrrolidinone (1.80 mL) was added p-chlorobenzylamine(61, 0.20 g, 1.4 mmol). The reaction was irradiated with microwave on300 watts, 150° C. for 15 minutes, then poured into water and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated and purified bysilica gel column chromatography eluting with 20% to 100% ethyl acetatein hexane to give the desired compound (613, 0.05 g, 74%). MS (ESI)[M+H⁺]⁺=524.3.

Step 2—Synthesis of(4-chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-0260)

To[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-chloro-benzyl)-amine(613, 0.050 g, 0.095 mmol) in tetrahydrofuran (10.0 mL) was addedtetrabutylammonium fluoride, trihydrate (0.20 g, 0.63 mmol) under anatmosphere of nitrogen. The reaction was stirred at room temperatureovernight, then poured into water, and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and washed with ethyl acetate in hexane togive an off-white solid (P-0260, 16.9 mg, 46%). MS (ESI) [M+H⁺]⁺=385.9.

Additional compounds were prepared following the protocol of Scheme 192,substituting p-chlorobenzylamine 61 with a suitable amine in Step 1. Thefollowing compounds were prepared following this protocol:

-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,6-difluoro-benzyl)-amine    (P-0261),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0262),-   (2-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0263),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-benzyl)-amine    (P-0264),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,4-difluoro-benzyl)-amine    (P-0265),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)-amine    (P-0266),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,5-difluoro-benzyl)-amine    (P-0267), and-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-trifluoromethyl-benzyl)-amine    (P-0268).    The following table indicates the amine (Column 2) used in Scheme    192 to provide the compounds (Column 3). Column 1 provides the    compound number and Column 4 the experimental mass spectrometry    result.

MS (ESI) Compound [M + H⁺]⁺ number Amine in Step 1 Compound observedP-0261

384.1 P-0262

418.9 P-0263

384.2 P-0264

368.2 P-0265

386.2 P-0266

418.9 P-0267

[M − H⁺]⁻ = 384.0 P-0268

419.2

Example 76 Synthesis of(2-fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amineP-0291

(2-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amineP-0291 was synthesized in 1 step from1-benzenesulfonyl-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine612 as shown in Scheme 193.

Step 1—Synthesis of(2-fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-0291)

To1-benzenesulfonyl-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(612, 0.080 g, 0.19 mmol, prepared as described in Example 74, Scheme191) in N-methylpyrrolidinone (1.00 mL) was added2-fluoro-5-trifluoromethyl-benzylamine (614, 0.20 g, 1.0 mmol). Thereaction was irradated with microwave on 300 watts, 150° C. for 15minutes. Potassium hydroxide in water (1.00 M, 2.00 mL) was added to thereaction. The reaction was irradiated with microwave on 300 watts, 90°C. for 10 minutes, then poured into water and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated and purified by silica gelcolumn chromatography eluting with 20% to 100% ethyl acetate in hexaneto give a white solid (P-0291, 37.4 mg, 50%). MS (ESI) [M+H⁺]⁺=402.6.

Additional compounds were prepared following the protocol of Scheme 193,substituting 2-fluoro-5-trifluoromethyl-benzylamine 614 with a suitableamine. The following compounds were prepared following this protocol:

-   (2,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0292),-   (2-Chloro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0293),-   (3-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0294),-   (3,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0295),-   (2-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0300),-   (2-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0301),-   [5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0302),-   [5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-benzyl)-amine    (P-0303),-   (5-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0304),-   (2,4-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0305),-   (2,4-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0306),-   (4-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0307),-   [5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)-amine    (P-0308),-   (2-Fluoro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0309),-   (2,5-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0310),-   (3-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0311),-   (2-Difluoromethoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0312),-   (2,3-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0313),-   (4-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0314),-   (5-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0315),-   (2-Chloro-4-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0316),-   (5-Chloro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0317),-   (5-Fluoro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0318),-   (2-Fluoro-4-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0319),-   (4-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0320), and-   (2-Chloro-5-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0407).    The following table indicates the amine (Column 2) used in Scheme    193 to provide the compounds (Column 3). Column 1 provides the    compound number and Column 4 the experimental mass spectrometry    result.

MS (ESI) Compound [M + H⁺]⁺ number Amine Compound observed P-0292

352.3 P-0293

418.2 P-0294

402.5 P-0295

352.3 P-0300

334.5 P-0301

349.9 P-0302

384.0 P-0303

400.5 P-0304

367.9 P-0305

383.9 P-0306

352.4 P-0307

352.0 P-0308

384.0 P-0309

402.5 P-0310

389.0 P-0311

368.0 P-0312

382.5 P-0313

385.0 P-0314

367.9 P-0315

402.4 P-0316

368.2 P-0317

364.8 P-0318

348.6 P-0319

402.5 P-0320

402.5 P-0407

368.3

Example 77 Synthesis of[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-difluoromethoxy-benzyl)-amineP-0390

[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-difluoromethoxy-benzyl)-amineP-0390 was synthesized in 1 step from1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine610 as shown in Scheme 194.

Step 1—Synthesis of[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-difluoromethoxy-benzyl)-amine(P-0390)

To1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(610, 0.060 g, 0.13 mmol, prepared as described in Example 74, Scheme191) in N-methylpyrrolidinone (1.40 mL) was added2-difluoromethoxy-benzylamine

(615, 0.200 g, 1.16 mmol). The reaction was irradiated with microwave on300 watts, 150° C. for 15 minutes. Potassium hydroxide in water (1.00 M,2.00 mL) was added to the reaction. The reaction was irradiated withmicrowave on 300 watts, 90° C. for 10 minutes, then poured into ethylacetate and water. The organic layer was concentrated and purified bysilica gel column chromatography eluting with 20% to 100% ethyl acetatein hexane to give a white solid (P-0390, 10.9 mg, 20%). MS (ESI)[M+H⁺]⁺=418.0.

Additional compounds were prepared following the protocol of Scheme 194,substituting 2-difluoromethoxy-benzylamine 615 with a suitable amine.The following compounds were prepared following this protocol:

-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-5-trifluoromethyl-benzyl)-amine    (P-0289),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-2-trifluoromethyl-benzyl)-amine    (P-0391),-   (3-Chloro-2-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0392),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-3-trifluoromethyl-benzyl)-amine    (P-0393),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-4-trifluoromethyl-benzyl)-amine    (P-0394),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,3-difluoro-benzyl)-amine    (P-0395),-   (2-Chloro-4-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0396),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-benzyl)-amine    (P-0402),-   (2-Chloro-5-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0408),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-4-ylmethyl-amine    (P-0416),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-pyrrolidin-1-yl-ethyl)-amine    (P-0417),-   Benzyl-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0418),-   Benzyl-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methyl-amine    (P-0419),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethoxy-benzyl)-amine    (P-0420),-   (3-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0421),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-3-ylmethyl-amine    (P-0422),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluoro-benzyl)-amine    (P-0423),-   (3-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methyl-amine    (P-0424),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3,5-difluoro-benzyl)-amine    (P-0425),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[1-(2-fluoro-phenyl)-ethyl]-amine    (P-0426),-   [1-(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0427),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[(S)-1-(4-fluoro-phenyl)-ethyl]-amine    (P-0428),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0429),-   (2-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methyl-amine    (P-0430),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methyl-benzyl)-amine    (P-0431),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-benzyl)-amine    (P-0433),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)-amine    (P-0434),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohexylmethyl-amine    (P-0435),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-2-ylmethyl-amine    (P-0436),-   [2-(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0437),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-difluoromethoxy-benzyl)-amine    (P-0438),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methoxy-benzyl)-amine    (P-0439),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-benzyl)-amine    (P-0440),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-ethyl)-amine    (P-0441),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-fluoro-benzyl)-amine    (P-0442),-   (3-Chloro-4-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0443),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-ethoxy-benzyl)-amine    (P-0444),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-morpholin-4-yl-benzyl)-amine    (P-0445),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-difluoromethoxy-benzyl)-amine    (P-0446),-   (4-Chloro-3-fluoro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-0447),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[1-(3-fluoro-phenyl)-ethyl]-amine    (P-0448), and-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-dimethylamino-benzyl)-amine    (P-0449).    The following table indicates the amine (Column 2) used in Scheme    194 to provide the compounds (Column 3). Column 1 provides the    compound number and Column 4 the experimental mass spectrometry    result.

Com- MS (ESI) pound [M + H⁺]⁺ number Amine Compound observed P-0289

436.0 P-0391

436.0 P-0392

402.0 P-0393

[M − H⁺]⁻ = 434.1 P-0394

437.3 P-0395

386.0 P-0396

402.0 P-0402

434.3 P-0408

402.0 P-0416

351.1 P-0417

357.1 P-0418

350.3 P-0419

364.3 P-0420

434.3 P-0421

383.9 P-0422

351.1 P-0423

368.3 P-0424

398.3 P-0425

386.3 P-0426

382.3 P-0427

398.3 P-0428

382.3 P-0429

419.1 P-0430

397.9 P-0431

364.3 P-0433

380.3 P-0434

373.1 P-0435

356.3 P-0436

351.1 P-0437

397.9 P-0438

416.3 P-0439

380.3 P-0440

364.3 P-0441

317.9 P-0442

368.3 P-0443

401.9 P-0444

393.9 P-0445

435.1 P-0446

416.3 P-0447

402.3 P-0448

382.3 P-0449

393.1

Example 78 Synthesis of(2-chloro-6-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0210

(2-Chloro-6-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0210 was synthesized in 2 steps from5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine600 as shown in Scheme 195.

Step 1—Preparation of[5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-chloro-6-fluoro-benzyl)-amine(617)

5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine(600, 30 mg, 0.083 mmol, prepared as described in Example 68, Scheme185) was combined with 2-chloro-6-fluoro-benzaldehyde (616, 26.2 mg,0.165 mmol) in a 2 mL microwave reaction vial. The mixture was dissolvedin ethanol:acetic acid (95:5, 0.6 mL). Silica supported cyanoborohydride(1.0 mmol/g, 83 mg, 0.083 mmol) was added and the mixture was irradiatedwith microwave on 300 watts for 5 minutes at 100° C. The silica wasseparated by centrifuging and the supernatant solution was decanted. Thesilica residue was rinsed with ethanol (0.500 mL) and centrifuged. Thesolvents were combined and removed under reduced pressure to givecompound 617, which was used in the next step without furtherpurification.

Step 2—Preparation of(2-chloro-6-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-0210)

[5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-chloro-6-fluoro-benzyl)-amine617 was combined with methanol:potassium hydroxide (1M) (1:1, 0.5 mL).The mixture was heated at 80° C. for 2 hours. Acetic acid (0.1 mL) wasadded and the solvents removed under reduced pressure. The remainingresidue was dissolved in dimethylsulfoxide (0.4 mL) and purified byreverse phase HPLC on a Phenomenex column (50 mm×10 mm ID) eluting with0.1% trifluoroacetic acid in water and 20-100% acetonitrile with 0.1%trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute toprovide the desired compound P-0210. MS (ESI) [M+H⁺]⁺=367.1.

Additional compounds were prepared following the protocol of Scheme 195,replacing 2-chloro-6-fluoro-benzaldehyde 616 with an appropriatealdehyde in Step 1. The following compounds were made following thisprocedure:

-   Phenethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0211),-   (2,4-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0212),-   (2-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0213),-   (3-Bromo-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0214),-   (2-Methoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0215),-   (2-Chloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0216),-   (2-Methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0217),-   (1-Methyl-1H-benzoimidazol-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0218),-   (6-Methoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0219),-   (1H-Benzoimidazol-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0220),-   (2-Chloro-4-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0221),-   (5-Methoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0222),-   (3-Fluoro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0223),-   (6-Methoxy-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0224),-   (4-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0225),-   [5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0226),-   (3,5-Dichloro-pyridin-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0227),-   (6-Morpholin-4-yl-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0228),-   (3-Fluoro-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0229),-   (5-Fluoro-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0230),-   (2,4-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0342),-   (3-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0343),-   (2-Fluoro-4-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0344),-   (4-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0345),-   (3-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0346),-   (2-Morpholin-4-yl-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0347),-   (4-Chloro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0348),-   (2-Chloro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0349),-   (2-Fluoro-5-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]amine    (P-0350),-   (2,3-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0351),-   (2-Fluoro-3-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0352),-   Dimethyl-(5-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyrimidin-2-yl)-amine    (P-0353),-   (3-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0354),-   (5-Fluoro-pyridin-2-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0355),-   (3,5-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0356),-   (2-Propoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0357),-   (2-Morpholin-4-yl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0358),-   (2-Chloro-3-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0359),-   (2-Fluoro-6-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0360),-   [2-(2-Morpholin-4-yl-ethoxy)-benzyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0361),-   (2,3-Difluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0362),-   (2-Chloro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0363),-   (2-Chloro-5-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0364),-   (2-Fluoro-3-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0365),-   (5-Fluoro-2-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0366),-   (2-Difluoromethoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0367),-   (2-Fluoro-4-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0368),-   [2-(3-Dimethylamino-propoxy)-benzyl]-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0369),-   (2,6-Dimethoxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0370),-   (2-Fluoro-5-methoxy-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0371),-   (4-Fluoro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0372),-   (3-Chloro-5-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0373),-   (6-Cyclopentyloxy-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0374),-   (5-Fluoro-2-trifluoromethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0375),-   [5-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-[2-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-amine    (P-0376),-   Propane-1-sulfonic acid    (2-fluoro-3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-phenyl)-amide    (P-0377),-   (2,5-Dichloro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0380),-   Pyrimidin-5-ylmethyl-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0381),-   (5-Chloro-2-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0382),-   (2-Ethyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0383),    2,2-Dimethyl-N-(3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-propionamide    (P-0384),-   Methyl-(3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-amine    (P-0385),-   Methyl-(5-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyrimidin-2-yl)-amine    (P-0386),-   (2-Chloro-4-methanesulfonyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0387),-   (5-Fluoro-2-methyl-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0397),-   (2,2-Difluoro-benzo[1,3]dioxol-4-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0398),-   Dimethyl-(3-{[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-amine    (P-0399),-   (5-Chloro-pyridin-3-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0400), and-   (2-Methoxy-pyrimidin-5-ylmethyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-0401).    The following table indicates the aldehyde (Column 2) used in Step 1    of Scheme 195 to provide the compounds (Column 3). Column 1 provides    the compound number and Column 4 the experimental mass spectrometry    result.

Com- MS(ESI) pound [M + H⁺]⁺ number Aldehyde Compound observed P-0211

329.1 P-0212

351.1 P-0213

338.1 P-0214

395.9 P-0215

345.9 P-0216

349.1 P-0217

329.1 P-0218

369.1 P-0219

345.9 P-0220

355.1 P-0221

367.1 P-0222

345.9 P-0223

334.3 P-0224

345.9 P-0225

401.1 P-0226

383.1 P-0227

383.9 P-0228

401.1 P-0229

334.3 P-0230

334.3 P-0342

383.1 P-0343

333.1 P-0344

401.1 P-0345

367.1 P-0346

401.1 P-0347

401.1 P-0348

417.1 P-0349

417.1 P-0350

401.1 P-0351

383.1 P-0352

363.1 P-0353

360.3 P-0354

367.1 P-0355

334.3 P-0356

351.1 P-0357

373.1 P-0358

400.3 P-0359

379.1 P-0360

401.1 P-0361

444.3 P-0362

351.1 P-0363

417.1 P-0364

367.1 P-0365

401.1 P-0366

363.1 P-0367

381.1 P-0368

347.1 P-0369

416.3 P-0370

376.3 P-0371

363.1 P-0372

347.1 P-0373

367.1 P-0374

400.3 P-0375

401.1 P-0376

413.9 P-0377

453.9 P0380

383.1 P-0381

317.2 P-0382

367.1 P-0383

343.1 P-0384

415.2 P-0385

345.4 P-0386

345.2 P-0387

427.1 P-0397

347.1 P-0398

396.1 P-0399

359.1 P-0400

350.3 P-0401

347.1

Example 79 Synthesis of[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amineP-0190

[4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amineP-0190 was synthesized in 2 steps from5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine592 as shown in Scheme 196.

Step 1—Preparation of[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3ylmethyl)-4-chloro-thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine(619)

5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine(592, 30 mg, 0.083 mmol, prepared as described in Example 66, Scheme183) was combined with 6-methoxy-pyridine-3-carbaldehyde (618, 26.2 mg,0.165 mmol) in a 2 mL microwave reaction vial. The mixture was dissolvedin ethanol: acetic acid (95:5, 0.6 mL). Silica supportedcyanoborohydride (1.0 mmol/g, 83 mg, 0.083 mmol) was added and themixture was irradiated with microwave on 300 watts for 5 minutes at 100°C. The silica was separated by centrifuging and the supernatant solutionwas decanted. The silica residue was rinsed with ethanol (0.500 mL) andcentrifuged. The solvents were combined and removed under reducedpressure to give the desired compound 619, which was used withoutfurther purification.

Step 11—Preparation of[4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine(P-0190)

[5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine619 was combined with methanol: potassium hydroxide (1M) (1:1, 0.5 mL).The mixture was heated at 80° C. for 2 hours. Acetic acid (0.1 mL) wasadded and the solvents removed under reduced pressure. The remainingresidue was dissolved in dimethylsulfoxide (0.4 mL) and purified byreverse phase HPLC on a Phenomenex column (50 mm×10 mm ID) eluting with0.1% trifluoroacetic acid in water and 20-100% acetonitrile with 0.1%trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute toprovide the desired compound P-0190. MS (ESI) [M+H⁺]⁺=419.9.

Additional compounds were prepared following the protocol of Scheme 196,replacing 6-methoxy-pyridine-3-carbaldehyde 618 with a suitable aldehydein Step 1. The following compounds were made following this procedure:

-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-thiazol-2-ylmethyl-amine    (P-0189),-   Benzyl-[4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine    (P-0192),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-methoxy-benzyl)-amine    (P-0193),-   (4-Chloro-benzyl)-[4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine    (P-0194),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine    (P-0195),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5-ylmethyl)-amine    (P-0196),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H-imidazol-4-ylmethyl)-amine    (P-0197),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-2H-pyrazol-3-ylmethyl)-amine    (P-0198),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-2-ylmethyl)-amine    (P-0199),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-4-ylmethyl)-amine    (P-0200),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-thiazol-4-ylmethyl)-amine    (P-0201),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-methyl-thiazol-5-ylmethyl)-amine    (P-0202),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-chloro-pyridin-2-ylmethyl)-amine    (P-0203),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl-amine    (P-0236),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amine    (P-0237),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-chloro-pyridin-4-ylmethyl)-amine    (P-0238),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(1-ethyl-1H-pyrazol-4-ylmethyl)-amine    (P-0239),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-2-ylmethyl)-amine    (P-0240),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3-ylmethyl)-amine    (P-0241),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine    (P-0242),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-6-fluoro-benzyl)-amine    (P-0243),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-phenethyl-amine    (P-0244),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-difluoro-benzyl)-amine    (P-0245),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-fluoro-benzyl)-amine    (P-0246),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methoxy-pyridin-3-ylmethyl)-amine    (P-0247),-   (2-Chloro-benzyl)-[4-chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine    (P-0248),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-benzyl)-amine    (P-0249),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-4-fluoro-benzyl)-amine    (P-0250),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-2-ylmethyl)-amine    (P-0251),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-morpholin-4-yl-pyridin-2-ylmethyl)-amine    (P-0252),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3,5-dichloro-pyridin-4-ylmethyl)-amine    (P-0253),-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-trifluoromethyl-benzyl)-amine    (P-0254), and-   [4-Chloro-5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2-ylmethyl)-amine    (P-0255).    The following table indicates the aldehyde (Column 2) used in Step 1    of Scheme 196 to provide the compounds (Column 3). Column 1 provides    the compound number and Column 4 the experimental mass spectrometry    result.

MS(ESI) Compound [M + H⁺]⁺ number Aldehyde Compound observed P-0189

395.9 P-0192

389.1 P-0193

419.1 P-0194

425.1 P-0195

407.1 P-0196

423.9 P-0197

421.1 P-0198

407.1 P-0199

419.9 P-0200

407.9 P-0201

409.9 P-0202

409.9 P-0203

423.9 P-0236

390.3 P-0237

390.3 P-0238

425.9 P-0239

407.1 P-0240

407.9 P-0241

419.9 P-0242

458.3 P-0243

443.1 P-0244

403.1 P-0245

424.7 P-0246

407.1 P-0247

419.9 P-0248

424.7 P-0249

403.1 P-0250

441.1 P-0251

407.9 P-0252

475.1 P-0253

459.9 P-0254

457.1 P-0255

404.3

Additional compounds were prepared following the protocol of Scheme 196,replacing5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine592 with5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine593 (prepared as described in Example 66, Scheme 183) in addition toreplacing 6-methoxy-pyridine-3-carbaldehyde 618 with a suitable aldehydein Step 1. The following compounds were made following this procedure:

-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5-ylmethyl)-amine    (P-0204),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H-imidazol-4-ylmethyl)-amine    (P-0205),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-2-ylmethyl)-amine    (P-0206),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3-ylmethyl)-amine    (P-0207),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4,5-dimethyl-thiophen-2-ylmethyl)-amine    (P-0208),-   [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,5-dimethyl-thiophen-3-ylmethyl)-amine    (P-0209),    The following table indicates the aldehyde (Column 2) used in Step 1    of Scheme 196 to provide the compounds (Column 3). Column 1 provides    the compound number and Column 4 the experimental mass spectrometry    result.

MS(ESI) Compound [M + H⁺]⁺ number Aldehyde Compound observed P-0204

390.3 P-0205

387.1 P-0206

373.9 P-0207

386.3 P-0208

389.1 P-0209

389.1

Example 80 Synthesis of5-[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-pyridin-2-yl-(4-trifluoromethyl-benzyl)-amineP-0388

5-[1-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-pyridin-2-yl-(4-trifluoromethyl-benzyl)-amineP-0388 was synthesized from(5-bromo-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine 17 as shown inScheme 197.

Step 1—Preparation of1-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-ethanone (620)

(5-Bromo-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine (17, 3.00 g,9.06 mmol, prepared as described in Example 10, Scheme 12) was dissolvedin tetrahydrofuran (80 mL). The reaction was cooled at −78° C. under anatmosphere of argon. 2.5 M n-butyllithium in hexane (10.9 mL) was added.The reaction was stirred at −78° C. for 60 minutes.N-Methoxy-N-methylacetamide (1.93 mL, 18.1 mmol) was added to thereaction, which was allowed to warm to room temperature. The reactionwas poured into 1M ammonium chloride and brine and extracted with ethylacetate. The organic portions were dried with anhydrous sodium sulfate,filtered and the filtrate was adsorbed onto silica. The mixture waspurified by silica gel chromatography (ethyl acetate:hexanes) to providethe desired compound as an oil that crystallized to a white solid (620,1.328 g, 50%), consistent with the compound structure by ¹H-NMR and MS(ESI): [M+H⁺]⁺=295.3.

Step 2—Preparation of(5-acetyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acidtert-butyl ester (621)

To 1-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-ethanone (620,1.30 g, 4.42 mmol) in tetrahydrofuran (15.0 mL) were addeddi-tert-butyldicarbonate (1.10 g, 5.04 mmol), 4-dimethylaminopyridine(0.0259 g, 0.21 mmol) and N,N-diisopropylethylamine (0.888 mL, 5.10mmol) under an atmosphere of nitrogen. The reaction was stirred at roomtemperature for 3 days. The mixture was extracted with ethyl acetate andsaturated sodium bicarbonate. The organic portions were dried withanhydrous sodium sulfate, filtered and the filtrate was adsorbed ontosilica. The mixture was purified by silica gel chromatography (0-15%ethyl acetate:hexanes) to provide the desired compound as an oil thatsolidified to a white solid (621, 1.29 g, 74%), consistent with thecompound structure by ¹H-NMR.

Step 3—Preparation of1-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-1-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanol(622)

3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 485.9 mg,1.21 mmol) was dissolved in tetrahydrofuran (8 mL) at −20° C. under anatmosphere of nitrogen. 2.0 M isopropylmagnesium chloride intetrahydrofuran (0.655 mL) was added. The reaction was stirred at −20°C. for 1 hour. Into the reaction was added(5-acetyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acidtert-butyl ester (621, 300.0 mg, 0.76 mmol) in tetrahydrofuran (6 mL)The reaction was allowed to warm to room temperature overnight. Themixture was extracted with ethyl acetate and saturated sodiumbicarbonate. The organic portions were dried with anhydrous sodiumsulfate, filtered and the filtrate was adsorbed onto silica. The mixturewas purified by silica gel chromatography on the (ethylacetate:hexanes), to provide the desired compound as an oil (622, 125mg, 29%), consistent with the compound structure by ¹H-NMR.

Step 4—Preparation of5-[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-vinyl]-pyridin-2-yl-(4-trifluoromethyl-benzyl)-amine(623)

1-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-yl]-1-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanol(622, 125.0 mg, 0.22 mmol) was dissolved in acetonitrile (11.7 mL) andtrifluoroacetic acid (0.175 mL, 2.3 mmol) and triethylsilane (0.292 mL,1.8 mmol) were added. The reaction was heated to reflux overnight. Thereaction was concentrated, then washed with ethyl acetate and saturatedsodium bicarbonate. The organic portions were dried with anhydroussodium sulfate, filtered and the filtrate was adsorbed onto silica. Themixture was purified by silica gel chromatography (0-60% ethylacetate:hexanes) to provide the desired compound (623, 43 mg, 50%),consistent with the compound structure by ¹H-NMR.

Step 5—Preparation of5-[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-pyridin-2-yl-(4-trifluoromethyl-benzyl)-amine(P-0388):

5-[1-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-vinyl]-pyridin-2-yl-(4-trifluoromethyl-benzyl)-amine(623, 0.043 g, 0.00011 mol) was dissolved in tetrahydrofuran (10 mL) andmethanol (10 mL). The reaction was shaken under an atmosphere ofhydrogen (30 psi) overnight. The reaction was filtered through Celiteand the filtrate adsorbed onto silica and purified by silica gel columnchromatography (ethyl acetate:hexanes) to provide the desired compoundas a white solid (P-0388, 2.1 mg, 5%), consistent with compoundstructure by ¹H-NMR and MS (ESI): [M+H⁺]⁺=397.6.

Example 81 Synthesis of[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amineP-0290

[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amineP-0290 was synthesized in four steps from(4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acidtert-butyl ester 624 as shown in Scheme 198.

Step 1—Preparation of(4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acidtert-butyl ester (625)

To a solution of(4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acidtert-butyl ester (624, 1 g, 2.70 mmol, prepared as described in Example44, Scheme 159, Step 2, where 4-(aminomethyl)pyridine 516 is replacedwith p-fluorobenzylamine, i.e. intermediate in preparing compoundP-0156) in methanol (100 mL) was added Pd/C (100 mg, 50% water wet) andsodium acetate (660 mg, 8.09 mmol) and the mixture was shaken under anatmosphere of hydrogen (50 psi) overnight observing ˜50% conversion byLC/MS. The mixture was filtered over a bed of Celite and the solvent wasremoved in vacuo and the residue purified by silica gel chromatography(ethyl acetate/heptane) to provide the desired compound as an off-whitesolid (450 mg, 50%), consistent with compound structure by ¹H-NMR.

Step 2—Preparation of{5-[(5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-thiazol-2-yl}-(4-fluoro-benzyl)-carbamicacid tert-butyl ester (627)

To a solution of5-chloro-3-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (626,300 mg, 0.69 mmol) in tetrahydrofuran (10 mL) at −20° C. was addeddropwise iso-propyl-magnesium chloride (2M in tetrahydrofuran, 0.44 mL,0.88 mmol). The reaction mixture was allowed to warm to 0° C. over 10minutes and then cooled to −40° C. To this reaction mixture was added asolution of (4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamicacid tert-butyl ester (625, 211 mg, 0.63 mmol) in tetrahydrofuran (5mL). The reaction mixture was allowed to warm to 0° C. over 30 minutesand then quenched with brine (50 mL). The mixture was transferred to aseparatory funnel and the layers were separated. The organic layer wasdried over sodium sulfate and evaporated in vacuo to give the crudematerial which was purified by silica gel column chromatography (0-30%ethyl acetate/heptane) to provide the desired compound as a foam (120mg, 30%), consistent with structure by ¹H-NMR.

Step 3—Preparation of[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-carbamicacid tert-butyl ester (628)

To a solution of{5-[(5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-thiazol-2-yl}-(4-fluoro-benzyl)-carbamicacid tert-butyl ester (627, 120 mg, 0.186 mmol) in acetonitrile (3 mL)was added trifluoroacetic acid (0.14 mL, 1.86 mmol) and triethylsilane(0.30 mL, 1.86 mmol). The resulting mixture was stirred for 2 hours at40° C. The solvent was then removed in vacuo and the residue was useddirectly in the next step.

Step 4: Preparation of[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine(P-0290)

To the solution of crude[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-carbamicacid tert-butyl ester (628, 0.186 mmol theory) in dichloromethane (5 mL)at room temperature was added trifluoroacetic acid (1 mL) and thereaction was allowed to stir overnight. The solvent was removed in vacuoand the residue taken up in ethyl acetate and then washed with saturatedaqueous potassium carbonate making sure basicity was reached. The layerswere separated and the aqueous layer was back-extracted with ethylacetate. The combined organic layers were dried over sodium sulfate andevaporated in vacuo to give the crude product which was purified bysilica gel chromatography (0-10% methanol/ethyl acetate). The solventwas removed in vacuo and the material was triturated withdichloromethane to give the desired compound as an off-white solid (20mg, 29% over 2 steps) consistent with compound structure by ¹H-NMR and

MS (ESI): [M+H⁺]⁺=372.9.

(4-Fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amineP-0389

was synthesized following the protocol of Scheme 198, replacing5-chloro-3-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine 626 with3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 96, to providethe desired compound, consistent with structure by 1H-NMR and MS (ESI):[M+H⁺]⁺=339.0.

Example 82 Synthesis of(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]-methanoneP-0184

(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]-methanoneP-0184 was synthesized from 5-chloro-1H-pyrrolo[2,3-b]pyridine 532 in 1step as shown in Scheme 199.

Step 1—Synthesis of(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]-methanone(P-0184)

5-Chloro-1H-pyrrolo[2,3-b]pyridine (532, 0.068 g, 0.44 mmol) wascombined with methanol (10 mL) and potassium hydroxide (0.16 g, 2.8mmol). The mixture was stirred for 50 minutes, then2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 0.100g, 0.40 mmol, prepared as described in Example 47, Scheme 162, Step 5)was added and the reaction was stirred overnight at room temperature andthen concentrated. Ethyl acetate was added and the mixture was washedwith sodium bicarbonate saturated solution and brine. After drying overanhydrous sodium sulfate the solvent was removed under reduced pressure.Purification with silica gel column chromatography eluting with agradient of ethyl acetate (10-100%) in hexanes provided the desiredcompound (0.0033 g, 2%). MS (ESI) [M+H⁺]⁺=398.1.

Example 83 Synthesis of[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-ethyl-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amineP-0185

[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-ethyl-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amineP-0185 was synthesized from5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 629 in 2steps as shown in Scheme 200.

Step 1—Synthesis of(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]-methanol(630)

5-Chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (629,0.15 g, 0.34 mmol) was dissolved in tetrahydrofuran (3 mL, 40 mmol) andthe solution was cooled to −20° C. 2 M isopropylmagnesium chloride intetrahydrofuran (200 μL) was added dropwise and the reaction was stirredand allowed to warm to −5° C. After the reaction was cooled to −20° C.,2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 0.043g, 0.17 mmol, prepared as described in Example 47, Scheme 162, Step 5)in tetrahydrofuran (4 mL) was added to the mixture. The reaction wasstirred to −5° C., then concentrated, ethyl acetate was added and themixture was washed with sodium bicarbonate saturated solution and brine.After drying over anhydrous sodium sulfate, the solvent was removedunder reduced pressure. Purification with silica gel columnchromatography eluting with a gradient of ethyl acetate (5-80%) inhexanes gave the desired compound (630, 0.038 g, 40%).

Step 2—Synthesis of5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-ethyl-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine(P-0185)

(5-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]-methanol(630, 0.045 g, 0.081 mmol) was dissolved in acetonitrile (5 mL) andtriethylsilane (0.4 mL, 2.0 mmol) was added, followed by trifluoroaceticacid (0.2 mL, 2.0 mmol). The reaction was stirred at room temperaturefor 45 minutes, then stirred at 60° C. for 45 minutes. The solvent wasremoved under reduced pressure, ethyl acetate was added and the organicwas washed with sodium bicarbonate saturated solution and brine. Afterdrying over anhydrous sodium sulfate, the solvent was evaporated todryness. Purification with silica gel column chromatography eluting witha gradient of ethyl acetate (40-100%) in hexanes gave the isolation ofthe desired compound (P-0185, 0.0068 g, 22%). MS (ESI) [M+H⁺]⁺=384.1.

Example 84 Synthesis of3-2-Fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrileP-0415

3-2-Fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrileP-0415 was synthesized in 5 steps from1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile 632 as shown in Scheme 201.

Step 1—Synthesis of3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (633)

To 1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile (632, 3.00 g, 0.0210 mol) inisopropyl alcohol (120 mL) were added dimethylamine hydrochloride (1.91g, 0.0235 mol) and formaldehyde (0.708 g, 0.0236 mol). The reaction washeated to reflux overnight, then concentrated, poured into water, andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography eluting with 5% to 30% methanol indichloromethane containing 0.3% triethyl amine to give the desiredcompound (633, 2.0 g, 48%).

Step 2—Synthesis of5-cyano-3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester (634)

To 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (633,2.0 g, 0.010 mol) in tetrahydrofuran (60.0 mL) were addeddi-tert-butyldicarbonate (2.62 g, 0.0120 mol), 4-dimethylaminopyridine(0.12 g, 0.0010 mol) and triethylamine (4.0 mL, 0.029 mol). The reactionwas stirred at 45° C. over a weekend, then concentrated, poured intoaqueous potassium carbonate, and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography eluting with 2% to 30% methanol in dichloromethane inhexane to give the desired compound (634, 2.50 g, 83%).

Step 3—Synthesis of3-chloromethyl-5-cyano-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester (635)

To 5-cyano-3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylicacid tert-butyl ester (634, 2.60 g, 8.66 mmol) in toluene (60.0 mL)under an atmosphere of nitrogen was added ethyl chloroformate (0.828 mL,8.66 mmol). The reaction was stirred at room temperature for 3 hours,then poured into water and extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated and purified by silica gel column chromatographyeluting with 20% to 100% ethyl acetate in hexane to give a white solid(635, 400 mg, 16%).

Step 4—Synthesis of[5-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester (636)

To(5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester (631, 0.600 g, 1.50 mmol, prepared as described inExample 60) in tetrahydrofuran (10.0 mL) at −25° C. under an atmosphereof nitrogen, was added a solution of isopropylmagnesium chloride (2.0 Min tetrahydrofuran, 0.730 mL). The reaction was allowed to warm to 5° C.over 1 hour. The reaction was cooled to −35° C., followed by addition ofa solution of CuCN.2LiCl (0.65 M in tetrahydrofuran, 2.4 mL). After 5minutes, 3-chloromethyl-5-cyano-pyrrolo[2,3-b]pyridine-1-carboxylic acidtert-butyl ester (635, 0.086 g, 0.29 mmol) in tetrahydrofuran (4.0 mL)was added to the reaction. The reaction was allowed to warm to roomtemperature over 1 hour, then poured into a diluted ammonia solution,and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified by silica gel column chromatography eluting with 20% to 100%ethyl acetate in hexane to give the desired compound (636, 0.13 g, 92%).MS (ESI) [M+H⁺]⁺=477.4.

Step 5—Synthesis of3-2-fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile(P-0415)

To[5-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester (636, 0.130 g, 0.27 mmol) in dichloromethane (10.0mL) was added trifluoroacetic acid (1.00 mL, 0.0130 mol). The reactionwas stirred at room temperature overnight. The reaction wasconcentrated, poured into aqueous potassium carbonate, and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated and purified bysilica gel column chromatography eluting with 25% to 100% ethyl acetatein hexane to give a white solid (P-0415, 85.6 mg, 83.4%). MS (ESI)[M+H⁺]⁺=377.0.

(5-Fluoro-pyridin-3-ylmethyl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-0414

was prepared following the protocol of Scheme 201, replacing1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile 632 with1H-Pyrrolo[2,3-b]pyridine in Step 1. MS (ESI) [M+H⁺]⁺=352.5.

3-[6-(4-Chloro-benzylamino)-2-fluoro-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrileP-0432

was prepared following the protocol of Scheme 201, replacing5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester 631 with(5-Bromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-carbamic acidtert-butyl ester 637 (prepared as described in Example 60) in Step 4. MS(ESI) [M+H⁺]⁺=391.9.

Example 85 Synthesis of(3-chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-amineP-0410

(3-Chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-amineP-0410 was synthesized in 11 steps from 1H-pyrazole-3,5-dicarboxylicacid monohydrate 638 as shown in Scheme 202.

Step 1—Preparation of 1H-pyrazole-3,5-dicarboxylic acid dimethyl ester(639)

1H-Pyrazole-3,5-dicarboxylic acid monohydrate (638, 21.1 g, 121.0 mmol)was combined with methanol (350 mL) and hydrogen chloride (10 mL). Thereaction was stirred at reflux overnight and then concentrated. Theresulting solid was washed with ethyl acetate and hexanes and driedunder reduced pressure. The obtained compound 639 was used withoutfurther purification. MS (ESI) [M+H⁺]⁺=185.0.

Step 2—Preparation of 1-methyl-1H-pyrazole-3,5-dicarboxylic aciddimethyl ester (640)

1H-Pyrazole-3,5-dicarboxylic acid dimethyl ester (639, 9.1 g, 49.0 mmol)was combined with acetone (400 mL) and potassium carbonate (10.2 g, 74.1mmol). The mixture was stirred for 40 minutes under an atmosphere ofnitrogen. To the stirring suspension, methyl iodide (3.4 mL, 54.0 mmol)was added dropwise. The reaction was stirred at room temperatureovernight and then the solvent was evaporated under reduced pressure.The resulting solid was washed with water and filtered. After toluenewas added, the solvent was removed under reduced pressure. The resultingcompound 640 was used without further purification.

Step 3—Preparation of 1-methyl-1H-pyrazole-3,5-dicarboxylic acid5-methyl ester (641)

1-Methyl-1H-pyrazole-3,5-dicarboxylic acid dimethyl ester (640, 3.7 g,19.0 mmol) was combined with 1,4-dioxane (20 mL) and water (60 mL).Concentrated sulfuric acid (1.0 mL) in 2 mL of water was added to thesolution. After the reaction was stirred at reflux overnight, it wascooled to room temperature and concentrated until precipitation began.The obtained mixture was left standing overnight. The resulting solidwas filtered and dried under reduced pressure. The collected aqueousfractions were extracted with ethyl acetate. The organic portion wasdried over anhydrous sodium sulfate and concentrated. Additional solidwas crystallized from ethyl acetate to give the desired compound (641,2.33 g, 68%). MS (ESI) [M+H⁺]⁺=185.0, melting point 175° C.

Step 4—Preparation of 5-azidocarbonyl-2-methyl-2H-pyrazole-3-carboxylicacid methyl ester (642)

1-Methyl-1H-pyrazole-3,5-dicarboxylic acid 5-methyl ester (641, 3.2 g,17.0 mmol) was combined with thionyl chloride (5 mL). The reaction washeated to reflux for 40 minutes and then concentrated twice fromtoluene. The resulting solid was dried under reduced pressure overnight.The product was dissolved into acetone (20 mL) and sodium azide (3.5 g,54.0 mmol) was added in water (10 mL) rapidly at once. The obtainedsolution was stirred for one minute and then poured into ice-water (50mL). The precipitate was filtered and dried under reduced pressure. Thefinal compound was used without further purification (642, 2.8 g, 77%).

Step 5—Preparation of5-benzyloxycarbonylamino-2-methyl-2H-pyrazole-3-carboxylic acid methylester (643)

5-Azidocarbonyl-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester(642, 2.8 g, 13.0 mmol) was combined with toluene (35 mL) and benzylalcohol (2.1 mL, 20.0 mmol). The reaction was heated to reflux for 45minutes and then the solvent was removed under reduced pressure. Thecompound (643, 2.4 g, 62%) was washed with methanol and dried undervacuum. MS (ESI) [M+H⁺]⁺=290.3.

Step 6—Preparation of 5-amino-2-methyl-2H-pyrazole-3-carboxylic acidmethyl ester (644)

5-Benzyloxycarbonylamino-2-methyl-2H-pyrazole-3-carboxylic acid methylester (643, 2.2 g, 7.6 mmol) was combined with methanol (50 mL) and 10%palladium on carbon (500 mg). The mixture was stirred under anatmosphere of hydrogen for three hours. The mixture was filtered throughCelite and the solvent was removed under reduced pressure to give thedesired compound (644, 1.2 g, 98%). (ESI) [M+H⁺]⁺=156.1.

Step 7—Preparation of5-(3-chloro-benzylamino)-2-methyl-2H-pyrazole-3-carboxylic acid methylester (646)

5-Amino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (644, 1.3 g,8.0 mmol) was combined with 3-chlorobenzaldehyde (645, 0.95 mL, 8.4mmol) and acetonitrile (40 mL). Trifluoroacetic acid (3.2 mL, 42.0 mmol)was added followed by triethylsilane (6.7 mL, 42.0 mmol). The reactionwas heated to reflux overnight and then concentrated. Ethyl acetate wasadded and the solution was washed with 1N potassium carbonate. Theorganic portion was dried over anhydrous sodium sulfate, filtered andconcentrated. The compound (646, 0.944 g, 42%) was crystallized from amixture of ethyl acetate:hexane.

Step 8—Preparation of[5-(3-chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-methanol (647)

5-(3-Chloro-benzylamino)-2-methyl-2H-pyrazole-3-carboxylic acid methylester (646, 0.944 g, 3.37 mmol) was combined with tetrahydrofuran (20mL) and the solution was cooled to −40° C. 1.0 M lithiumtetrahydroaluminate in tetrahydrofuran (3.7 mL) was added and thereaction was stirred for 45 min at −20° C. 1.0 M lithiumtetrahydroaluminate in tetrahydrofuran (3.7 mL) was added at −40° C. andthe reaction was stirred to 10° C. Sodium sulfate decahydrate was addedin small portions and the mixture was stirred for two hours at roomtemperature, then filtered through Celite and concentrated. Theresulting compound (647, 0.821 g, 97%) was washed with a mixture ofethyl acetate:hexanes and dried under reduced pressure.

Step 9—Preparation of5-(3-chloro-benzylamino)-2-methyl-2H-pyrazole-3-carbaldehyde (648)

[5-(3-Chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-methanol (647, 0.821g, 3.26 mmol) was combined with dichloromethane (70 mL) andmanganese(IV) oxide (4 g). The reaction was stirred at room temperatureovernight under an atmosphere of nitrogen. The mixture was filteredthrough Celite and concentrated. Purification by silica gel columnchromatography eluting with a gradient of ethyl acetate (10-100%) inhexane gave the desired aldehyde (648, 0.482 g, 60%).

Step 10—Preparation of[5-(3-chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-(5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(649)

5-Chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (629,0.19 g, 0.44 mmol) was dissolved in tetrahydrofuran (0.9 mL). Thesolution was cooled to −20° C. 2M isopropylmagnesium chloride intetrahydrofuran (200 μL) was added dropwise to the mixture, then stirredto −5° C. After the reaction was cooled to −20° C.,5-(3-chloro-benzylamino)-2-methyl-2H-pyrazole-3-carbaldehyde (648, 0.050g, 0.20 mmol) in 2 mL of tetrahydrofuran was added at once to themixture. The reaction was stirred to 0° C. and then concentrated. Ethylacetate was added and the mixture was washed with sodium bicarbonatesaturated solution and brine. The organic portion was dried overanhydrous sodium sulfate and concentrated. Purification with silica gelcolumn chromatography eluting with a gradient of ethyl acetate (5-80%)in hexane gave the desired compound (649, 0.033 g, 30%). (ESI)[M+H⁺]⁺=558.3, 560.9.

Step 11—Preparation of(3-chloro-benzyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-amine(P-0410)

[5-(3-Chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-(5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(649, 0.033 g, 0.059 mmol) was combined with dichloromethane (5 mL, 0.08mol) and triethylsilane (200 μL, 1.0 mmol) was added, followed bytrifluoroacetic acid (100 μL, 1.0 mmol). The reaction was stirred atroom temperature overnight and then concentrated. Ethyl acetate wasadded and the organic portion was washed with 1 M potassium carbonate,dried over anhydrous sodium sulfate and concentrated. Purification withsilica gel flash chromatography eluting with a gradient of methanol(2-20%) and dichloromethane followed by washes with a mixture of ethylacetate:hexane gave the desired compound (P-0410, 0.0039 g, 17%). (ESI)[M+H⁺]⁺=387.30.

[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-(2,5-difluoro-benzyl)-amineP-0411 and[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-(2-fluoro-benzyl)-amineP-0413,

were prepared following the protocol of Scheme 202, replacing3-chlorobenzaldehyde 645 with 2,5-difluorobenzaldehyde and2-fluorobenzaldehyde, respectively, in Step 7. (ESI) [M+H⁺]⁺=389.95(P-0411) and 370.20 (P-0413).

Example 86 Additional Compounds

The following compounds of the invention were synthesized following themethods of the Examples above, or similar methods known to those ofskill in the art:

-   3-(6-tert-Butoxy-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine    (P-0020),-   3-(6-Methoxy-pyridin-3-ylmethyl)-4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine    (P-0022),-   (6-Isobutylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol    (P-0029),-   [6-(Cyclopropylmethyl-amino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol    (P-0034),-   [6-(Cyclohexylmethyl-amino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol    (P-0035),-   (1H-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-methanol    (P-0036),-   [6-(4-Chloro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol    (P-0037),-   (4-Chloro-benzyl)-{5-[methoxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-amine    (P-0039),-   (4-Chloro-3-trifluoromethyl-benzyl)-{5-[methoxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-amine    (P-0040),-   (4-Chloro-benzyl)-{5-[methoxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-amine    (P-0041),-   [6-(4-Chloro-benzylamino)-2-methyl-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol    (P-0046),-   [2,6-Bis-(4-chloro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-0049), and-   3-(2-Ethylsulfanyl-4,6-dimethyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine    (P-0052).

All patents and other references cited in the specification areindicative of the level of skill of those skilled in the art to whichthe invention pertains, and are incorporated by reference in theirentireties, including any tables and figures, to the same extent as ifeach reference had been incorporated by reference in its entiretyindividually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to obtain the ends and advantages mentioned,as well as those inherent therein. The methods, variances, andcompositions described herein as presently representative of preferredembodiments are exemplary and are not intended as limitations on thescope of the invention. Changes therein and other uses will occur tothose skilled in the art, which are encompassed within the spirit of theinvention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications may be made to the invention disclosedherein without departing from the scope and spirit of the invention. Forexample, variations can be made to provide additional compounds ofFormulae I, II or III, and all sub-embodiments thereof, and/or variousmethods of administration can be used. Thus, such additional embodimentsare within the scope of the present invention and the following claims.

The invention illustratively described herein suitably may be practicedin the absence of any element or elements, limitation or limitationswhich is not specifically disclosed herein. The terms and expressionswhich have been employed are used as terms of description and not oflimitation, and there is no intention that in the use of such terms andexpressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the invention claimed.Thus, it should be understood that although the present invention hasbeen specifically disclosed by preferred embodiments and optionalfeatures, modification and variation of the concepts herein disclosedmay be resorted to by those skilled in the art, and that suchmodifications and variations are considered to be within the scope ofthis invention as defined by the appended claims.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member or subgroup of members of the Markushgroup or other group.

Also, unless indicated to the contrary, where various numerical valuesare provided for embodiments, additional embodiments are described bytaking any 2 different values as the endpoints of a range. Such rangesare also within the scope of the described invention.

Thus, additional embodiments are within the scope of the invention andwithin the following claims.

SEQUENCE LISTING SEQ ID NO: 1 Sequence NP_000213Met Arg Gly Ala Arg Gly Ala Trp Asp Phe Leu Cys Val Leu LeuLeu Leu Leu Arg Val Gln Thr Gly Ser Ser Gln Pro Ser Val SerPro Gly Glu Pro Ser Pro Pro Ser Ile His Pro Gly Lys Ser AspLeu Ile Val Arg Val Gly Asp Glu Ile Arg Leu Leu Cys Thr AspPro Gly Phe Val Lys Trp Thr Phe Glu Ile Leu Asp Glu Thr AsnGlu Asn Lys Gln Asn Glu Trp Ile Thr Glu Lys Ala Glu Ala ThrAsn Thr Gly Lys Tyr Thr Cys Thr Asn Lys His Gly Leu Ser AsnSer Ile Tyr Val Phe Val Arg Asp Pro Ala Lys Leu Phe Leu ValAsp Arg Ser Leu Tyr Gly Lys Glu Asp Asn Asp Thr Leu Val ArgCys Pro Leu Thr Asp Pro Glu Val Thr Asn Tyr Ser Leu Lys GlyCys Gln Gly Lys Pro Leu Pro Lys Asp Leu Arg Phe Ile Pro AspPro Lys Ala Gly Ile Met Ile Lys Ser Val Lys Arg Ala Tyr HisArg Leu Cys Leu His Cys Ser Val Asp Gln Glu Gly Lys Ser ValLeu Ser Glu Lys Phe Ile Leu Lys Val Arg Pro Ala Phe Lys AlaVal Pro Val Val Ser Val Ser Lys Ala Ser Tyr Leu Leu Arg GluGly Glu Glu Phe Thr Val Thr Cys Thr Ile Lys Asp Val Ser SerSer Val Tyr Ser Thr Trp Lys Arg Glu Asn Ser Gln Thr Lys LeuGln Glu Lys Tyr Asn Ser Trp His His Gly Asp Phe Asn Tyr GluArg Gln Ala Thr Leu Thr Ile Ser Ser Ala Arg Val Asn Asp SerGly Val Phe Met Cys Tyr Ala Asn Asn Thr Phe Gly Ser Ala AsnVal Thr Thr Thr Leu Glu Val Val Asp Lys Gly Phe Ile Asn IlePhe Pro Met Ile Asn Thr Thr Val Phe Val Asn Asp Gly Glu AsnVal Asp Leu Ile Val Glu Tyr Glu Ala Phe Pro Lys Pro Glu HisGln Gln Trp Ile Tyr Met Asn Arg Thr Phe Thr Asp Lys Trp GluAsp Tyr Pro Lys Ser Glu Asn Glu Ser Asn Ile Arg Tyr Val SerGlu Leu His Leu Thr Arg Leu Lys Gly Thr Glu Gly Gly Thr TyrThr Phe Leu Val Ser Asn Ser Asp Val Asn Ala Ala Ile Ala PheAsn Val Tyr Val Asn Thr Lys Pro Glu Ile Leu Thr Tyr Asp ArgLeu Val Asn Gly Met Leu Gln Cys Val Ala Ala Gly Phe Pro GluPro Thr Ile Asp Trp Tyr Phe Cys Pro Gly Thr Glu Gln Arg CysSer Ala Ser Val Leu Pro Val Asp Val Gln Thr Leu Asn Ser SerGly Pro Pro Phe Gly Lys Leu Val Val Gln Ser Ser Ile Asp SerSer Ala Phe Lys His Asn Gly Thr Val Glu Cys Lys Ala Tyr AsnAsp Val Gly Lys Thr Ser Ala Tyr Phe Asn Phe Ala Phe Lys GlyAsn Asn Lys Glu Gln Ile His Pro His Thr Leu Phe Thr Pro LeuLeu Ile Gly Phe Val Ile Val Ala Gly Met Met Cys Ile Ile ValMet Ile Leu Thr Tyr Lys Tyr Leu Gln Lys Pro Met Tyr Glu ValGln Trp Lys Val Val Glu Glu Ile Asn Gly Asn Asn Tyr Val TyrIle Asp Pro Thr Gln Leu Pro Tyr Asp His Lys Trp Glu Phe ProArg Asn Arg Leu Ser Phe Gly Lys Thr Leu Gly Ala Gly Ala PheGly Lys Val Val Glu Ala Thr Ala Tyr Gly Leu Ile Lys Ser AspAla Ala Met Thr Val Ala Val Lys Met Leu Lys Pro Ser Ala HisLeu Thr Glu Arg Glu Ala Leu Met Ser Glu Leu Lys Val Leu SerTyr Leu Gly Asn His Met Asn Ile Val Asn Leu Leu Gly Ala CysThr Ile Gly Gly Pro Thr Leu Val Ile Thr Glu Tyr Cys Cys TyrGly Asp Leu Leu Asn Phe Leu Arg Arg Lys Arg Asp Ser Phe IleCys Ser Lys Gln Glu Asp His Ala Glu Ala Ala Leu Tyr Lys AsnLeu Leu His Ser Lys Glu Ser Ser Cys Ser Asp Ser Thr Asn GluTyr Met Asp Met Lys Pro Gly Val Ser Tyr Val Val Pro Thr LysAla Asp Lys Arg Arg Ser Val Arg Ile Gly Ser Tyr Ile Glu ArgAsp Val Thr Pro Ala Ile Met Glu Asp Asp Glu Leu Ala Leu AspLeu Glu Asp Leu Leu Ser Phe Ser Tyr Gln Val Ala Lys Gly MetAla Phe Leu Ala Ser Lys Asn Cys Ile His Arg Asp Leu Ala AlaArg Asn Ile Leu Leu Thr His Gly Arg Ile Thr Lys Ile Cys AspPhe Gly Leu Ala Arg Asp Ile Lys Asn Asp Ser Asn Tyr Val ValLys Gly Asn Ala Arg Leu Pro Val Lys Trp Met Ala Pro Glu SerIle Phe Asn Cys Val Tyr Thr Phe Glu Ser Asp Val Trp Ser TyrGly Ile Phe Leu Trp Glu Leu Phe Ser Leu Gly Ser Ser Pro TyrPro Gly Met Pro Val Asp Ser Lys Phe Tyr Lys Met Ile Lys GluGly Phe Arg Met Leu Ser Pro Glu His Ala Pro Ala Glu Met TyrAsp Ile Met Lys Thr Cys Trp Asp Ala Asp Pro Leu Lys Arg ProThr Phe Lys Gln Ile Val Gln Leu Ile Glu Lys Gln Ile Ser GluSer Thr Asn His Ile Tyr Ser Asn Leu Ala Asn Cys Ser Pro AsnArg Gln Lys Pro Val Val Asp His Ser Val Arg Ile Asn Ser ValGly Ser Thr Ala Ser Ser Ser Gln Pro Leu Leu Val His Asp Asp ValSEQ ID NO: 2 Sequence NM_000222   1 gatcccatcg cagctaccgc gatgagaggc gctcgcggcg cctgggattt tctctgcgtt  61 ctgctcctac tgcttcgcgt ccagacaggc tcttctcaac catctgtgag tccaggggaa 121 ccgtctccac catccatcca tccaggaaaa tcagacttaa tagtccgcgt gggcgacgag 181 attaggctgt tatgcactga tccgggcttt gtcaaatgga cttttgagat cctggatgaa 241 acgaatgaga ataagcagaa tgaatggatc acggaaaagg cagaagccac caacaccggc 301 aaatacacgt gcaccaacaa acacggctta agcaattcca tttatgtgtt tgttagagat 361 cctgccaagc ttttccttgt tgaccgctcc ttgtatggga aagaagacaa cgacacgctg 421 gtccgctgtc ctctcacaga cccagaagtg accaattatt ccctcaaggg gtgccagggg 481 aagcctcttc ccaaggactt gaggtttatt cctgacccca aggcgggcat catgatcaaa 541 agtgtgaaac gcgcctacca tcggctctgt ctgcattgtt ctgtggacca ggagggcaag 601 tcagtgctgt cggaaaaatt catcctgaaa gtgaggccag ccttcaaagc tgtgcctgtt 661 gtgtctgtgt ccaaagcaag ctatcttctt agggaagggg aagaattcac agtgacgtgc 721 acaataaaag atgtgtctag ttctgtgtac tcaacgtgga aaagagaaaa cagtcagact 781 aaactacagg agaaatataa tagctggcat cacggtgact tcaattatga acgtcaggca 841 acgttgacta tcagttcagc gagagttaat gattctggag tgttcatgtg ttatgccaat 901 aatacttttg gatcagcaaa tgtcacaaca accttggaag tagtagataa aggattcatt 961 aatatcttcc ccatgataaa cactacagta tttgtaaacg atggagaaaa tgtagatttg1021 attgttgaat atgaagcatt ccccaaacct gaacaccagc agtggatcta tatgaacaga1081 accttcactg ataaatggga agattatccc aagtctgaga atgaaagtaa tatcagatac1141 gtaagtgaac ttcatctaac gagattaaaa ggcaccgaag gaggcactta cacattccta1201 gtgtccaatt ctgacgtcaa tgctgccata gcatttaatg tttatgtgaa tacaaaacca1261 gaaatcctga cttacgacag gctcgtgaat ggcatgctcc aatgtgtggc agcaggattc1321 ccagagccca caatagattg gtatttttgt ccaggaactg agcagagatg ctctgcttct1381 gtactgccag tggatgtgca gacactaaac tcatctgggc caccgtttgg aaagctagtg1441 gttcagagtt ctatagattc tagtgcattc aagcacaatg gcacggttga atgtaaggct1501 tacaacgatg tgggcaagac ttctgcctat tttaactttg catttaaagg taacaacaaa1561 gagcaaatcc atccccacac cctgttcact cctttgctga ttggtttcgt aatcgtagct1621 ggcatgatgt gcattattgt gatgattctg acctacaaat atttacagaa acccatgtat1681 gaagtacagt ggaaggttgt tgaggagata aatggaaaca attatgttta catagaccca1741 acacaacttc cttatgatca caaatgggag tttcccagaa acaggctgag ttttgggaaa1801 accctgggtg ctggagcttt cgggaaggtt gttgaggcaa ctgcttatgg cttaattaag1861 tcagatgcgg ccatgactgt cgctgtaaag atgctcaagc cgagtgccca tttgacagaa1921 cgggaagccc tcatgtctga actcaaagtc ctgagttacc ttggtaatca catgaatatt1981 gtgaatctac ttggagcctg caccattgga gggcccaccc tggtcattac agaatattgt2041 tgctatggtg atcttttgaa ttttttgaga agaaaacgtg attcatttat ttgttcaaag2101 caggaagatc atgcagaagc tgcactttat aagaatcttc tgcattcaaa ggagtcttcc2161 tgcagcgata gtactaatga gtacatggac atgaaacctg gagtttctta tgttgtccca2221 accaaggccg acaaaaggag atctgtgaga ataggctcat acatagaaag agatgtgact2281 cccgccatca tggaggatga cgagttggcc ctagacttag aagacttgct gagcttttct2341 taccaggtgg caaagggcat ggctttcctc gcctccaaga attgtattca cagagacttg2401 gcagccagaa atatcctcct tactcatggt cggatcacaa agatttgtga ttttggtcta2461 gccagagaca tcaagaatga ttctaattat gtggttaaag gaaacgctcg actacctgtg2521 aagtggatgg cacctgaaag cattttcaac tgtgtataca cgtttgaaag tgacgtctgg2581 tcctatggga tttttctttg ggagctgttc tctttaggaa gcagccccta tcctggaatg2641 ccggtcgatt ctaagttcta caagatgatc aaggaaggct tccggatgct cagccctgaa2701 cacgcacctg ctgaaatgta tgacataatg aagacttgct gggatgcaga tcccctaaaa2761 agaccaacat tcaagcaaat tgttcagcta attgagaagc agatttcaga gagcaccaat2821 catatttact ccaacttagc aaactgcagc cccaaccgac agaagcccgt ggtagaccat2881 tctgtgcgga tcaattctgt cggcagcacc gcttcctcct cccagcctct gcttgtgcac2941 gacgatgtct gagcagaatc agtgtttggg tcacccctcc aggaatgatc tcttcttttg3001 gcttccatga tggttatttt cttttctttc aacttgcatc caactccagg atagtgggca3061 ccccactgca atcctgtctt tctgagcaca ctttagtggc cgatgatttt tgtcatcagc3121 caccatccta ttgcaaaggt tccaactgta tatattccca atagcaacgt agcttctacc3181 atgaacagaa aacattctga tttggaaaaa gagagggagg tatggactgg gggccagagt3241 cctttccaag gcttctccaa ttctgcccaa aaatatggtt gatagtttac ctgaataaat3301 ggtagtaatc acagttggcc ttcagaacca tccatagtag tatgatgata caagattaga3361 agctgaaaac ctaagtcctt tatgtggaaa acagaacatc attagaacaa aggacagagt3421 atgaacacct gggcttaaga aatctagtat ttcatgctgg gaatgagaca taggccatga3481 aaaaaatgat ccccaagtgt gaacaaaaga tgctcttctg tggaccactg catgagcttt3541 tatactaccg acctggtttt taaatagagt ttgctattag agcattgaat tggagagaag3601 gcctccctag ccagcacttg tatatacgca tctataaatt gtccgtgttc atacatttga3661 ggggaaaaca ccataaggtt tcgtttctgt atacaaccct ggcattatgt ccactgtgta3721 tagaagtaga ttaagagcca tataagtttg aaggaaacag ttaataccat tttttaagga3781 aacaatataa ccacaaagca cagtttgaac aaaatctcct cttttagctg atgaacttat3841 tctgtagatt ctgtggaaca agcctatcag cttcagaatg gcattgtact caatggattt3901 gatgctgttt gacaaagtta ctgattcact gcatggctcc cacaggagtg ggaaaacact3961 gccatcttag tttggattct tatgtagcag gaaataaagt ataggtttag cctccttcgc4021 aggcatgtcc tggacaccgg gccagtatct atatatgtgt atgtacgttt gtatgtgtgt4081 agacaaatat ttggaggggt atttttgccc tgagtccaag agggtccttt agtacctgaa4141 aagtaacttg gctttcatta ttagtactgc tcttgtttct tttcacatag ctgtctagag4201 tagcttacca gaagcttcca tagtggtgca gaggaagtgg aaggcatcag tccctatgta4261 tttgcagttc acctgcactt aaggcactct gttatttaga ctcatcttac tgtacctgtt4321 ccttagacct tccataatgc tactgtctca ctgaaacatt taaattttac cctttagact4381 gtagcctgga tattattctt gtagtttacc tctttaaaaa caaaacaaaa caaaacaaaa4441 aactcccctt cctcactgcc caatataaaa ggcaaatgtg tacatggcag agtttgtgtg4501 ttgtcttgaa agattcaggt atgttgcctt tatggtttcc cccttctaca tttcttagac4561 tacatttaga gaactgtggc cgttatctgg aagtaaccat ttgcactgga gttctatgct4621 ctcgcacctt tccaaagtta acagattttg gggttgtgtt gtcacccaag agattgttgt4681 ttgccatact ttgtctgaaa aattcctttg tgtttctatt gacttcaatg atagtaagaa4741 aagtggttgt tagttataga tgtctaggta cttcaggggc acttcattga gagttttgtc4801 ttgccatact ttgtctgaaa aattcctttg tgtttctatt gacttcaatg atagtaagaa4861 aagtggttgt tagttataga tgtctaggta cttcaggggc acttcattga gagttttgtc4921 aatgtctttt gaatattccc aagcccatga gtccttgaaa atatttttta tatatacagt4981 aactttatgt gtaaatacat aagcggcgta agtttaaagg atgttggtgt tccacgtgtt5041 ttattcctgt atgttgtcca attgttgaca gttctgaaga attcSEQ ID NO: 3 Sequence NP_5202Met Gly Pro Gly Val Leu Leu Leu Leu Leu Val Ala Thr Ala TrpHis Gly Gln Gly Ile Pro Val Ile Glu Pro Ser Val Pro Glu LeuVal Val Lys Pro Gly Ala Thr Val Thr Leu Arg Cys Val Gly AsnGly Ser Val Glu Trp Asp Gly Pro Pro Ser Pro His Trp Thr LeuTyr Ser Asp Gly Ser Ser Ser Ile Leu Ser Thr Asn Asn Ala ThrPhe Gln Asn Thr Gly Thr Tyr Arg Cys Thr Glu Pro Gly Asp ProLeu Gly Gly Ser Ala Ala Ile His Leu Tyr Val Lys Asp Pro AlaArg Pro Trp Asn Val Leu Ala Gln Glu Val Val Val Phe Glu AspGln Asp Ala Leu Leu Pro Cys Leu Leu Thr Asp Pro Val Leu GluAla Gly Val Ser Leu Val Arg Val Arg Gly Arg Pro Leu Met ArgHis Thr Asn Tyr Ser Phe Ser Pro Trp His Gly Phe Thr Ile HisArg Ala Lys Phe Ile Gln Ser Gln Asp Tyr Gln Cys Ser Ala LeuMet Gly Gly Arg Lys Val Met Ser Ile Ser Ile Arg Leu Lys ValGln Lys Val Ile Pro Gly Pro Pro Ala Leu Thr Leu Val Pro AlaGlu Leu Val Arg Ile Arg Gly Glu Ala Ala Gln Ile Val Cys SerAla Ser Ser Val Asp Val Asn Phe Asp Val Phe Leu Gln His AsnAsn Thr Lys Leu Ala Ile Pro Gln Gln Ser Asp Phe His Asn AsnArg Tyr Gln Lys Val Leu Thr Leu Asn Leu Asp Gln Val Asp PheGln His Ala Gly Asn Tyr Ser Cys Val Ala Ser Asn Val Gln GlyLys His Ser Thr Ser Met Phe Phe Arg Val Val Glu Ser Ala TyrLeu Asn Leu Ser Ser Glu Gln Asn Leu Ile Gln Glu Val Thr ValGly Glu Gly Leu Asn Leu Lys Val Met Val Glu Ala Tyr Pro GlyLeu Gln Gly Phe Asn Trp Thr Tyr Leu Gly Pro Phe Ser Asp HisGln Pro Glu Pro Lys Leu Ala Asn Ala Thr Thr Lys Asp Thr TyrArg His Thr Phe Thr Leu Ser Leu Pro Arg Leu Lys Pro Ser GluAla Gly Arg Tyr Ser Phe Leu Ala Arg Asn Pro Gly Gly Trp ArgAla Leu Thr Phe Glu Leu Thr Leu Arg Tyr Pro Pro Glu Val SerVal Ile Trp Thr Phe Ile Asn Gly Ser Gly Thr Leu Leu Cys AlaAla Ser Gly Tyr Pro Gln Pro Asn Val Thr Trp Leu Gln Cys SerGly His Thr Asp Arg Cys Asp Glu Ala Gln Val Leu Gln Val TrpAsp Asp Pro Tyr Pro Glu Val Leu Ser Gln Glu Pro Phe His LysVal Thr Val Gln Ser Leu Leu Thr Val Glu Thr Leu Glu His AsnGln Thr Tyr Glu Cys Arg Ala His Asn Ser Val Gly Ser Gly SerTrp Ala Phe Ile Pro Ile Ser Ala Gly Ala His Thr His Pro ProAsp Glu Phe Leu Phe Thr Pro Val Val Val Ala Cys Met Ser IleMet Ala Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu Tyr Lys TyrLys Gln Lys Pro Lys Tyr Gln Val Arg Trp Lys Ile Ile Glu SerTyr Glu Gly Asn Ser Tyr Thr Phe Ile Asp Pro Thr Gln Leu ProTyr Asn Glu Lys Trp Glu Phe Pro Arg Asn Asn Leu Gln Phe GlyLys Thr Leu Gly Ala Gly Ala Phe Gly Lys Val Val Glu Ala ThrAla Phe Gly Leu Gly Lys Glu Asp Ala Val Leu Lys Val Ala ValLys Met Leu Lys Ser Thr Ala His Ala Asp Glu Lys Glu Ala LeuMet Ser Glu Leu Lys Ile Met Ser His Leu Gly Gln His Glu AsnIle Val Asn Leu Leu Gly Ala Cys Thr His Gly Gly Pro Val LeuVal Ile Thr Glu Tyr Cys Cys Tyr Gly Asp Leu Leu Asn Phe LeuArg Arg Lys Ala Glu Ala Met Leu Gly Pro Ser Leu Ser Pro GlyGln Asp Pro Glu Gly Gly Val Asp Tyr Lys Asn Ile His Leu GluLys Lys Tyr Val Arg Arg Asp Ser Gly Phe Ser Ser Gln Gly ValAsp Thr Tyr Val Glu Met Arg Pro Val Ser Thr Ser Ser Asn AspSer Phe Ser Glu Gln Asp Leu Asp Lys Glu Asp Gly Arg Pro LeuGlu Leu Arg Asp Leu Leu His Phe Ser Ser Gln Val Ala Gln GlyMet Ala Phe Leu Ala Ser Lys Asn Cys Ile His Arg Asp Val AlaAla Arg Asn Val Leu Leu Thr Asn Gly His Val Ala Lys Ile GlyAsp Phe Gly Leu Ala Arg Asp Ile Met Asn Asp Ser Asn Tyr IleVal Lys Gly Asn Ala Arg Leu Pro Val Lys Trp Met Ala Pro GluSer Ile Phe Asp Cys Val Tyr Thr Val Gln Ser Asp Val Trp SerTyr Gly Ile Leu Leu Trp Glu Ile Phe Ser Leu Gly Leu Asn ProTyr Pro Gly Ile Leu Val Asn Ser Lys Phe Tyr Lys Leu Val LysAsp Gly Tyr Gln Met Ala Gln Pro Ala Phe Ala Pro Lys Asn IleTyr Ser Ile Met Gln Ala Cys Trp Ala Leu Glu Pro Thr His ArgPro Thr Phe Gln Gln Ile Cys Ser Phe Leu Gln Glu Gln Ala GlnGlu Asp Arg Arg Glu Arg Asp Tyr Thr Asn Leu Pro Ser Ser SerArg Ser Gly Gly Ser Gly Ser Ser Ser Ser Glu Leu Glu Glu GluSer Ser Ser Glu His Leu Thr Cys Cys Glu Gln Gly Asp Ile AlaGln Pro Leu Leu Gln Pro Asn Asn Tyr Gln Phe CysSEQ ID NO: 4 Sequence NM_005211   1 gaagggcaga cagagtgtcc aaaagcgtga gagcacgaag tgaggagaag gtggagaaga  61 gagaagagga agaggaagag gaagagagga agcggaggga actgcggcca ggctaaaagg 121 ggaagaagag gatcagccca aggaggagga agaggaaaac aagacaaaca gccagtgcag 181 aggagaggaa cgtgtgtcca gtgtcccgat ccctgcggag ctagtagctg agagctctgt 241 gccctgggca ccttgcagcc ctgcacctgc ctgccacttc cccaccgagg ccatgggccc 301 aggagttctg ctgctcctgc tggtggccac agcttggcat ggtcagggaa tcccagtgat 361 agagcccagt gtccctgagc tggtcgtgaa gccaggagca acggtgacct tgcgatgtgt 421 gggcaatggc agcgtggaat gggatggccc cccatcacct cactggaccc tgtactctga 481 tggctccagc agcatcctca gcaccaacaa cgctaccttc caaaacacgg ggacctatcg 541 ctgcactgag cctggagacc ccctgggagg cagcgccgcc atccacctct atgtcaaaga 601 ccctgcccgg ccctggaacg tgctagcaca ggaggtggtc gtgttcgagg accaggacgc 661 actactgccc tgtctgctca cagacccggt gctggaagca ggcgtctcgc tggtgcgtgt 721 gcgtggccgg cccctcatgc gccacaccaa ctactccttc tcgccctggc atggcttcac 781 catccacagg gccaagttca ttcagagcca ggactatcaa tgcagtgccc tgatgggtgg 841 caggaaggtg atgtccatca gcatccggct gaaagtgcag aaagtcatcc cagggccccc 901 agccttgaca ctggtgcctg cagagctggt gcggattcga ggggaggctg cccagatcgt 961 gtgctcagcc agcagcgttg atgttaactt tgatgtcttc ctccaacaca acaacaccaa1021 gctcgcaatc cctcaacaat ctgactttca taataaccgt taccaaaaag tcctgaccct1081 caacctcgat caagtagatt tccaacatgc cggcaactac tcctgcgtgg ccagcaacgt1141 gcagggcaag cactccacct ccatgttctt ccgggtggta gagagtgcct acttgaactt1201 gagctctgag cagaacctca tccaggaggt gaccgtgggg gaggggctca acctcaaagt1261 catggtggag gcctacccag gcctgcaagg ttttaactgg acctacctgg gacccttttc1321 tgaccaccag cctgagccca agcttgctaa tgctaccacc aaggacacat acaggcacac1381 cttcaccctc tctctgcccc gcctgaagcc ctctgaggct ggccgctact ccttcctggc1441 cagaaaccca ggaggctgga gagctctgac gtttgagctc acccttcgat accccccaga1501 ggtaagcgtc atatggacat tcatcaacgg ctctggcacc cttttgtgtg ctgcctctgg1561 gtacccccag cccaacgtga catggctgca gtgcagtggc cacactgata ggtgtgatga1621 ggcccaagtg ctgcaggtct gggatgaccc ataccctgag gtcctgagcc aggagccctt1681 ccacaaggtg acggtgcaga gcctgctgac tgttgagacc ttagagcaca accaaaccta1741 cgagtgcagg gcccacaaca gcgtggggag tggctcctgg gccttcatac ccatctctgc1801 aggagcccac acgcatcccc cggatgagtt cctcttcaca ccagtggtgg tcgcctgcat1861 gtccatcatg gccttgctgc tgctgctgct cctgctgcta ttgtacaagt ataagcagaa1921 gcccaagtac caggtccgct ggaagatcat cgagagctat gagggcaaca gttatacttt1981 catcgacccc acgcagctgc cttacaacga gaagtgggag ttcccccgga acaacctgca2041 gtttggtaag accctcggag ctggagcctt tgggaaggtg gtggaggcca cggcctttgg2101 tctgggcaag gaggatgctg tcctgaaggt ggctgtgaag atgctgaagt ccacggccca2161 tgctgatgag aaggaggccc tcatgtccga gctgaagatc atgagccacc tgggccagca2221 cgagaacatc gtcaaccttc tgggagcctg tacccatgga ggccctgtac tggtcatcac2281 ggagtactgt tgctatggcg acctgctcaa ctttctgcga aggaaggctg aggccatgct2341 gggacccagc ctgagccccg gccaggaccc cgagggaggc gtcgactata agaacatcca2401 cctcgagaag aaatatgtcc gcagggacag tggcttctcc agccagggtg tggacaccta2461 tgtggagatg aggcctgtct ccacttcttc aaatgactcc ttctctgagc aagacctgga2521 caaggaggat ggacggcccc tggagctccg ggacctgctt cacttctcca gccaagtagc2581 ccagggcatg gccttcctcg cttccaagaa ttgcatccac cgggacgtgg cagcgcgtaa2641 cgtgctgttg accaatggtc atgtggccaa gattggggac ttcgggctgg ctagggacat2701 catgaatgac tccaactaca ttgtcaaggg caatgcccgc ctgcctgtga agtggatggc2761 cccagagagc atctttgact gtgtctacac ggttcagagc gacgtctggt cctatggcat2821 cctcctctgg gagatcttct cacttgggct gaatccctac cctggcatcc tggtgaacag2881 caagttctat aaactggtga aggatggata ccaaatggcc cagcctgcat ttgccccaaa2941 gaatatatac agcatcatgc aggcctgctg ggccttggag cccacccaca gacccacctt3001 ccagcagatc tgctccttcc ttcaggagca ggcccaagag gacaggagag agcgggacta3061 taccaatctg ccgagcagca gcagaagcgg tggcagcggc agcagcagca gtgagctgga3121 ggaggagagc tctagtgagc acctgacctg ctgcgagcaa ggggatatcg cccagccctt3181 gctgcagccc aacaactatc agttctgctg aggagttgac gacagggagt accactctcc3241 cctcctccaa acttcaactc ctccatggat ggggcgacac ggggagaaca tacaaactct3301 gccttcggtc atttcactca acagctcggc ccagctctga aacttgggaa ggtgagggat3361 tcaggggagg tcagaggatc ccacttcctg agcatgggcc atcactgcca gtcaggggct3421 gggggctgag ccctcacccc cccctcccct actgttctca tggtgttggc ctcgtgtttg3481 ctatgccaac tagtagaacc ttctttccta atccccttat cttcatggaa atggactgac3541 tttatgccta tgaagtcccc aggagctaca ctgatactga gaaaaccagg ctctttgggg3601 ctagacagac tggcagagag tgagatctcc ctctctgaga ggagcagcag atgctcacag3661 accacactca gctcaggccc cttggagcag gatggctcct ctaagaatct cacaggacct3721 cttagtctct gccctatacg ccgccttcac tccacagcct cacccctccc acccccatac3781 tggtactgct gtaatgagcc aagtggcagc taaaagttgg gggtgttctg cccagtcccg3841 tcattctggg ctagaaggca ggggaccttg gcatgtggct ggccacacca agcaggaagc3901 acaaactccc ccaagctgac tcatcctaac taacagtcac gccgtgggat gtctctgtcc3961 acattaaact aacagcatta atgca

What is claimed is:
 1. A compound of Formula IIa:

or a pharmaceutically acceptable salt, a tautomer or a stereoisomerthereof, wherein: A₃ is —CH₂— or —C(O)—; Q¹³ and Q¹⁴ are independentlyhydrogen, fluoro, chloro, lower alkyl, or fluoro substituted loweralkyl; Q¹² is fluoro, chloro or —CF₃ M₄ is —NHCH₂— or —NHC(O)—; Q^(1a)is aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from halogen, loweralkyl, fluoro substituted lower alkyl, cycloalkylamino, —NHR⁴¹,—NR⁴¹R⁴¹, —OR⁴¹ or —S(O)₂R⁴¹; and R⁴¹ at each occurrence isindependently lower alkyl or cycloalkyl, wherein lower alkyl isoptionally substituted with one or more fluoro; Q⁵ is —OR⁴³, —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl,heterocycloalkyl, aryl or heteroaryl are optionally substituted with oneor more substituents selected from halogen, lower alkyl, fluorosubstituted lower alkyl, —NHR⁴³, —NR⁴³R⁴³, —OR⁴³ or —S(O)₂R⁴³, whereinR⁴³ at each occurrence is independently optionally substituted loweralkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl or optionally substitutedhetereoaryl.
 2. The compound of claim 1, wherein: M₄ is —NHCH₂—; Q⁵ is—OR⁴³, —CN, C₁₋₃alkyl, fluoro substituted C₁₋₃alkyl, fluoro, chloro,aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, fluoro substituted lower alkyl,—NHR⁴³, —NR⁴³R⁴³, —OR⁴³ and —S(O)₂R⁴³; and Q³ and Q¹⁴ are hydrogen. 3.The compound of claim 1, wherein: Q^(1a) is aryl or heteroaryl, whereinaryl or heteroaryl are optionally substituted with one or moresubstituents selected from halogen, lower alkyl, fluoro substitutedlower alkyl, —NHR⁴¹, —NR⁴¹R⁴¹, or —OR⁴¹.
 4. The compound of claim 1,wherein: Q^(1a) is phenyl or pyridinyl, wherein phenyl or pyridinyl aresubstituted with 1 or 2 substituents selected from fluoro, chloro,methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy;and Q⁵ is —CN, fluoro, chloro, methyl, trifluoromethyl, methoxy,difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl orheteroaryl are optionally substituted with one or more halogen, loweralkyl, fluoro substituted lower alkyl, lower alkoxy, or fluorosubstituted lower alkoxy.
 5. The compound of claim 4, wherein Q^(1a) isphenyl mono substituted with chloro and Q⁵ is —CN, fluoro, chloro,methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy,aryl or heteroaryl, wherein aryl or heteroaryl are optionallysubstituted with one or more halogen, lower alkyl, fluoro substitutedlower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
 6. Thecompound of claim 1, wherein Q^(1a) is pyridin-3-yl monosubstituted withmethyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxyand Q⁵ is —CN, fluoro, chloro, methyl, trifluoromethyl, methoxy,difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl orheteroaryl are optionally substituted with one or more halogen, loweralkyl, fluoro substituted lower alkyl, lower alkoxy, or fluorosubstituted lower alkoxy.
 7. The compound of claim 1, wherein: Q^(1a) isphenyl or pyridinyl, wherein phenyl or pyridinyl are substituted with 1or 2 substituents selected from the group consisting of fluoro, chloro,methyl, methoxy, trifluoromethyl, difluoromethoxy and trifluoromethoxy;Q⁵ is fluoro, chloro, methyl, methoxy, trifluoromethyl,trifluoromethoxy, —CN, or 1-methyl-1H-pyrazole-4-yl; and Q¹² is fluoroor chloro; and Q¹³ and Q¹⁴ are hydrogen.
 8. The compound of claim 7,wherein Q^(1a) is phenyl substituted with one chloro and Q⁵ is chloro,methyl, methoxy, or —CN.
 9. The compound of claim 1, wherein: Q^(1a) ispyridin-3-yl monosubstituted with methyl, methoxy, trifluoromethyl,difluoromethoxy or trifluoromethoxy; Q⁵ is chloro, methyl, methoxy, —CN,or 1-methyl-1H-pyrazole-4-yl; Q¹² is fluoro or chloro; and Q¹³ and Q¹⁴are hydrogen.
 10. A compound of Formula III:

or a pharmaceutically acceptable salt, a tautomer or a stereoisomerthereof, wherein: L₄ is —CH₂ or —C(O)—; R⁸¹ is selected from —CN,fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, loweralkoxy, or fluoro substituted lower alkoxy; R⁸² is hydrogen, C₁₋₃alkyl,fluoro substituted C₂₋₃alkyl, OH, C₁₋₃alkoxy, or fluoro substitutedC₁₋₃alkoxy; R⁸³ is heteroaryl, wherein the heteroaryl is optionallysubstituted with one or two substituents selected from halogen, loweralkyl, fluoro substituted lower alkyl, cycloalkylamino, —NHR⁴¹,—NR⁴¹R⁴¹, —OR⁴¹ or —S(O)₂R⁴¹; and R⁴¹ at each occurrence isindependently lower alkyl or cycloalkyl, wherein lower alkyl isoptionally substituted with one or more fluoro.
 11. The compound ofclaim 10, wherein L⁴ is —CH₂.
 12. The compound of claim 10, wherein theheteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, isoxazolyl,imidazolyl, or benzimidazolyl.
 13. The compound of claim 10, wherein R⁸³is a heteroaryl optionally substituted with 1 or 2 substituentsindependently selected from fluoro, chloro, lower alkyl, fluorosubstituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy,or cycloalkylamino.
 14. The compound of claim 10, wherein R⁸³ is aheteroaryl optionally substituted with 1 or 2 substituents independentlyselected from fluoro, chloro, methyl, trifluoromethyl, methoxy ormorpholine.
 15. A pharmaceutical composition comprising apharmaceutically acceptable carrier or excipient and a compound ofclaim
 1. 16. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier excipient and a compound of claim 10.